CZ20002001A3 - Substituted imidazole derivatives with adrenergic alpha 2B or 2B / 2C agonist-like activity - Google Patents

Abstract

Compounds with adrenergic activity which are selective agonists for one or both of the alpha2B and alpha2C adrenoceptor receptor subtypes, which are preferred over the alpha2A adrenoceptor receptor subtype; the active compound is selected from the group consisting of compounds having formula I, wherein the dotted lines represent preferred bonds provided that two double bonds do not have to share a common carbon atom; R is H or lower alkyl; X is S or C(H)R', wherein R1 is H or lower alkyl, but R1 is absent if the bond between X and the ring represented by formula (a) is a double bond; Y is O, N, S, (CR12),,, where y is an integer from 1 to 3, -CH=CH- or Υ'ΟΕ-, wherein Y1 is O, N or S; x is 1 or 2, where x is 1 if R2, R3 or R4 are bonded to a saturated carbon atom and x is 2 if R2, R3 or R4 are bonded to a saturated carbon atom, R2 is H, lower alkyl, halogen, hydroxy, a hydroxy group or a lower alkoxy group, or phenyl, or together, are -(C(R2)x)z-; -Y’(C(R2)x)z'; -Y’(C(R2)x)yY'-; -C(R2)x)Y'-C(R2)x)-; -(C(R2)x)-Y'-(C(R2)x)-(C(R2)x)-and-Y'-(C(R2)x)-, where z is an integer from 3 to 5, z' is an integer from 2 to 4 and x and y are as defined above, and further both ends of each of these divalent moieties of the molecule can be attached to either R3 or R4 to form a fused ring structure and the rings formed can be fully unsaturated, partially unsaturated or fully saturated; and are useful for the treatment of muscle spasticity including hyperactive urinary frequency, diarrhea, urination, withdrawal syndromes, pain including neuropathic, neurodegenerative diseases, memory and consciousness disorders, psychosis including manic states and anxiety states, hypertension, congestive heart failure, cardiac ischemia and nasal congestion, without exhibiting sedative or cardiovascular side effects.

Description

Substituted imidazole derivatives with activity similar to alpha 2B or 2B/2C adrenergic receptor agonists. ’ *

Field of technology

and

The invention is directed to a method of treating glaucoma or elevated intraocular pressure and other diseases with a substantial reduction in cardiovascular or sedative side effects, by administering compounds that are selective agonists of either alpha2B alone or alpha2B and 2C adrenergic receptors, and that lack significant activity at the alpha2A receptor subtype, to mammals, including humans. The invention is also directed to novel compounds and pharmaceutical compositions adapted for administration of said compounds to mammals, including humans.

AND

State of the art

Compounds with adrenergic activity are well known in the art and are described in numerous U.S. and foreign patents, including scientific publications. It is generally known and accepted in the art that adrenergic activity is useful in the therapy of animals of mammalian species, including humans, for the treatment or amelioration of the symptoms and condition of a patient with a variety of diseases and conditions. In other words, it is generally accepted in the art that pharmaceutical compositions containing an adrenergic compound or compounds as an active ingredient are useful in the treatment of glaucoma, chronic pain, nasal congestion, high blood pressure, congestive heart failure, and induction of anesthesia.

The two main groups of adrenergic receptors are referred to in the art as alpha and beta adrenergic receptors, and each group includes subtypes, which are designated by the letters o

alphabets such as alpha2A, alpha2B. See Bylund et al., Pharmacol. Rev. 46, 121-136 (1994).

The essence of the invention

In accordance with the present invention, it has been found that adrenergic compounds that act selectively and preferentially, even specifically, as agonists of the alpha2B or alpha2B/alpha2C (herein referred to as alpha2B or alpha2B/2C) receptor subtypes, which they act preferentially on compared to the alpha2A receptor subtype, have desirable therapeutic properties similar to adrenergic agents, but without one or more of the adverse effects, such as changes in blood pressure or sedation. For the purposes of this invention, a compound is defined as a specific, or at least selective, agonist of the alpha2B or alpha2B/2C receptor subtypes if it is at least ten times more potent as an agonist of the alpha2B or alpha2C or both receptor subtypes than it is for the alpha2A receptor subtype, or if the difference in potency of the compound at the alpha2B and alpha2B/2C receptors compared to the alpha2A receptor is greater than 0.3 and its potency at the alpha2A receptor is less than or equal to 0.4.

Therefore, the invention relates to a method of treating animals of mammalian species, including humans, using a pharmaceutical composition comprising as an active ingredient one or more compounds having the activity of specific or selective alpha2B or alpha2B/2C agonists, used for the treatment of many diseases or conditions for which alpha adrenergic compounds are useful, including but not limited to glaucoma, decreased intraocular pressure, chronic pain, diarrhea and nasal congestion. Furthermore, the compounds of the invention are useful for the treatment of muscle spasticity including hyperactive urinary frequency, diarrhea, urination, withdrawal syndromes, pain, including neuropathic,

•i* j neurodegenerative diseases including optic neuropathy, spinal cord ischemia and stroke, memory and consciousness disorders, attention disorders, psychosis including manic states, anxiety states, depression, hypertension, congestive heart failure, cardiac ischemia and nasal congestion.

The present invention also includes pharmaceutical compositions used in the above-described method of treatment.

This invention relates in particular to a method of treating diseases and conditions in which adrenergic compounds are useful but their use is limited due to known adverse effects.

Detailed description of the invention

The compounds used in the pharmaceutical compositions and methods of treatment of the present invention are selective or specific agonists of the alpha2B or alpha2B/2C subtypes of adrenergic receptors, acting preferentially over the alpha2A receptor subtype. In accordance with the present invention, a compound is considered to be a selective alpha2B or alpha2C agonist if the difference in its potency as an agonist at the alpha2B or alpha2B/2C receptor subtypes compared to the alpha2A receptor subtype is greater than 0.3 and its potency at the alpha2A receptor subtype is less than or equal to 0.4 and/or is at least ten times less. Preferably, the compounds used in accordance with the present invention are specific agonists of the alpha2B or alpha2B/2C receptor subtypes. Specifically, a specific agonist is defined in this regard in the sense that the specific adrenergic agonist has no measurable or biologically significant effect on the alpha2A receptor subtype.

A number of compounds have been discovered that are functionally selective for the alpha2B or alpha2B/2C subtypes of these adrenergic receptors. Their preferential activity can be determined using a number of

f- ’ · 4 4 > ♦

Τ t of various functional assays such as cyclic AMP production, Shimizu et al., J.

Neurochem. 16, 1609-1619 (1969); R-SAT (receptor selection and amplification technique), Messier et al., Pharmacol. Toxicol. 76, 308-311 (1995) and cytosensor microphysiometer, Neve et al, J. Biol. Chem. 267, 25748-25753 (1992), using cells that naturally express the individual subtypes or one of the subtypes has been introduced into them. The cells or recombinant receptors used should be human or should belong to those species in which identical pharmacology has been demonstrated. In the study described below, the R-SAT assay was used on cells that were transiently transfected with human alpha2A (c10 gene), rat alpha2B (RNG gene) and human alpha2C (c4 gene) receptors. Rat alpha2B receptors have been shown to have pharmacology similar to human alpha2B receptors (see, for example, Bylund et al., Pharmacol. Rev. 46, 127-129 (1994)).

Topical administration is particularly useful in the treatment of glaucoma. Any topical formulation such as a solution, suspension, gel, ointment or cream, and the like, can be applied to the eye for glaucoma or to the skin for other indications. The preparation of such topical formulations is well described in the pharmaceutical arts, for example, in Remington's Pharmaceutical Science, 17th Edition, Mack Publishing Company, Easton, Pennsylvania.

If the drug is to be administered systemically, it can be prepared as powders, pills, tablets, and the like, as a syrup or elixir for oral administration. For intravenous, intraperitoneal, intrathecal, or epidural administration, the compound is prepared as a solution or suspension that can be injected. In certain cases, it may be useful to prepare these compounds as suppositories or as sustained-release depot preparations, including skin patches for placement on or under the skin, or as intramuscular injections.

The treatment of glaucoma or any other indication known or discovered to respond to treatment with adrenergic compounds is effected by administering a therapeutically effective dose of one or more of the compounds of this invention. A therapeutic concentration is a concentration that results in an improvement in a particular condition or retards its expansion. In some cases, the drug may be administered prophylactically to prevent the development of a particular condition. The therapeutic concentration administered will vary from case to case and will under certain circumstances depend on the severity of the condition being treated and the patient's responsiveness to the treatment. Accordingly, it is best to determine the therapeutic dose administered empirically, both in terms of time and space. However, it is believed that in the treatment of, for example, glaucoma, a preparation containing 0.001 to 5% by weight, preferably 0.01 to 3% by weight, will produce a therapeutically effective concentration. When administered systemically in an amount of 0.001 to 50 mg/kg, preferably 0.001 to 10 mg/kg of body weight per day, it will have a therapeutic effect in most cases.

Because compounds with alpha2B and alpha2B/2C specific selective agonist activity lack substantial alpha2A side effects, treatment of diseases or conditions with compounds of the present invention is particularly advantageous in humans with cardiovascular problems.

The general structure of examples of specific alpha2B and alpha2C agonists or adrenergic compounds with selective alpha2B and alpha2B/2C agonist activity that are used in the pharmaceutical compositions and therapeutic methods of the present invention is shown by the general formula below.

According to one aspect of the invention, a compound with selective agonist activity at the alpha2B or alpha2B/2C subtype(s) of adrenergic receptors is represented by the general formula ···· · · · ·

Y

R IN H where dotted lines represent preferred bonds, provided that two double bonds do not share a common carbon atom; R is H or lower alkyl; X is S or C(H)R ¹ , where R ¹ is H or lower alkyl, but R ¹ is absent if the bond between X and the ring represented is double; Y is O, N, S, (CR ¹ 2) _y , where y is an integer from 1 to 3, -CH=CH- or -Y ¹ CH ₂ - where Y ¹ is O, N, or S; x is an integer 1 or 2, where x is 1 when R ² , R ³ , or R ⁴ is bonded to an unsaturated carbon atom and x is 2 when R ² , R ³ , or R ⁴ is bonded to a saturated carbon atom;

R ² is H, lower alkyl, halogen, hydroxy and lower alkoxy, or, when attached to a saturated carbon atom, R ² is oxo; R ³ and R ⁴ are each H, lower alkyl, hydroxy, lower alkoxy or phenyl, or together -(C(R ² )x)z-; -Y ¹ (C(R ² )x)z'-; -Y ¹ (C(R ² )x)yY ¹ -; -(C(R ² )x)-Y ¹ -(C(R ² )x); (C(R ² )x)-Y ¹ -(C(R ² )x)-(C(R ² )x)-; and -Y ¹ -(C(R ² )x)-Y ¹ -(C(R ² )x), where z is an integer from 3 to 5, z' is an integer from 2 to 4, x and x are the same as defined above, and further both ends of each of these divalent moieties of the molecule can be attached to R ³ or R ⁴ to form a fused ring structure generally represented as

and the rings formed may be fully unsaturated, partially unsaturated, or fully saturated, provided that the carbon in the ring has no more than 4 valences, the nitrogen no more than 3 valences, and O and S no more than two valences.

In another aspect of the invention, the above compound is represented by the formula

where X can be C(H)R ¹ and R ¹ is H.

In said compound of formula II, R ² can be H and

may represent a furanyl radical.

In these furanyl derivatives of formula II, R ³ and R ⁴ can both be (CH) ₄ , or R ³ can be H and R ⁴ t-butyl, or R ³ and R ⁴ can be H, or R ³ can be H and R ⁴ methyl or ethyl.

Alternatively, R ¹ in a compound of formula I may be methyl and • ft • · »

» • ·

may represent a furanyl radical.

Alternatively, R ² in the compounds of formula II may be H and

may represent a thienyl radical.

In these thienyl derivatives of formula II, R ³ and R ⁴ may both be (CH 2 ) 4 , or R ³ may be phenyl and R ⁴ H, or R ³ and R ⁴ may both be represented by (CH 2 ) 3 S, or R ³ and R ⁴ may be H, or R ³ and R ⁴ may both be represented by (CH) 4 , or R ³ may be H and R ⁴ methyl, or R ³ may be bromo and R ⁴ H, or R ³ may be hydrogen and R ⁴ chlorine, or R ³ may be methyl and R ⁴ hydrogen.

Alternatively, in a compound of formula II,

represent a cyclohexyl radical.

In these cyclohexyl compounds of formula II, R ² may be hydrogen and R ³ and R ⁴ may both be represented by (CH) ₄ , or R ² may be an oxo group and R ³ and R ⁴ may both be (CH) ₄ , or R ² may be hydrogen or an oxo group and R ³ and R ⁴ may both be represented by (CH ₂ )S, or R ² may be hydrogen and R ³ and R ⁴ may both be represented by (CH ₂ ) ₄ , thus forming octahydronaphthalene, or R ² may be an oxo group and R ³ and R ⁴ may both be ···· · · s!

represented by (CH2)4, or R ² may be an oxo group and R ³ and R ⁴ may both be represented by (CH)2C(CH3)(CH), or R ² may be hydrogen and R ³ and R ⁴ may both be represented by S(CH2)2, or R ² , R ³ and R ⁴ may both be H, or R ² may be an oxo group and R ³ and R ⁴ may both be represented by (CH)2C(OCH3)CH, or R ³ and R ⁴ may both be represented by -Y ¹ -C(R ² )xC(R ² )xY ¹ -, where Y ¹ is N, thus forming a tetrahydroquinoxaline, where R ² may be hydrogen or an oxo group.

Alternatively, in compounds of formula II

may represent a tetrahydroquinoline radical where R ³ and R ⁴ are both -Y ¹ -C(R ² )xC(R ² )xC(R ² )X-, where Y ¹ is Ν. In these tetrahydroquinoline derivatives, (R ² )x may be hydrogen or an oxo group, or may represent a tetrahydroisoquinoline radical where R ³ and R ⁴ are both -C(R ² )xY ¹ -C(R ² )xC(R ² )x-, where Y ¹ is N and (R ² ) _x may be hydrogen or an oxo group.

Alternatively, in compounds of formula II

may represent a cyclopentyl radical.

In these cyclopentyl derivatives of formula II, R ² may be H and R ³ and R ⁴ may both be represented by (CH) ₄ , or R ² may be an oxo group and R ³ and R ⁴ may both be represented by (CH) 4 , or R ² may be hydrogen and R ³ and R ⁴ may both be represented by (CH 2 ) ₃ .

·· » « • · ···· · ·

Λ’

In another aspect of the invention, Y is (CH ₂ ) 3 and X can be CH and R ² is an oxo group, or X can be CH 2 and R ² can be H. Alternatively, R ³ and R ⁴ can both be represented by (CH) 4 , Y can be CH ₂ C(CR ¹ 2) ₂ , where R ¹ is hydrogen, or Y can be -CH ₂ C(Me)- and R ² can be hydrogen or an oxo group.

Finally, in compounds with formula II

can rearrange the phenyl radical.

In these phenyl derivatives of formula I, X may be CH ₂ , R may be H or CH ₃ , R ² , R ³ and R ⁴ may be H, or R ³ and R ⁴ may both be represented by O(CR ² ) ₂ O to form a 1,4-benzodioxane derivative, or alternatively X may be S and R ² , R ³ and R ⁴ may be H.

According to another aspect of the invention, said compound has the general formula

where Y is S or O.

In such a compound of formula III, XC can be (H)R ¹ , R, R ¹ , R ² , R ³ and R ⁴ can be H and Y can be O or S.

According to another aspect of the invention, said compound has the general formula

and R ³ and R ⁴ both represent (CH) ₄ .

In these compounds of formula IV, Y ¹ may be O, R ² is an oxo group and X is CH or CH 2 , or one of R ² is a hydroxy group and the other is H, or R ² may be H.

In these compounds of formula IV, Y ¹ can be S, X can be CH ₂ and R ² is an oxo group, or R ² can be H and X can be CH and R ² is an oxo group.

According to another aspect of the invention, a compound with selective activity at the 2B or 2B and 2C adrenergic receptor subtype(s) compared to the 2A adrenergic receptor subtype is represented by the general formula

alternatively, W is a bicyclic radical selected from the group consisting of

8 9998 •Ži • · 4 · • 8 99 · 8 · • 4 4 9 • · <5 » ·* 88 • 9 8 4 • 9 4 · • · 4 4 • · » 4 *· 98 where R ⁵ , R ⁶ , R ⁷ and R ⁸ are selected from the group consisting of H and lower alkyl, provided that at least one of R ⁵ and R ⁶ or R ⁶ and R ⁷ is OC(R ⁹ )C(R ⁹ )N(R), to form a fused ring

XX where R ⁹ is H, lower alkyl or oxo; and

wherein R ¹⁰ is H, lower alkyl, phenyl or lower alkyl substituted phenyl, and Z is O or NH. Compounds wherein W is norbornyl are described and claimed in commonly-claimed application Ser. No. 09/003902, filed January 7, 1998, which is hereby incorporated by reference in its entirety.

According to one aspect of the invention, Z can be O and W can be

and R ¹⁰ may be selected from the group consisting of H, phenyl or o-methylphenyl, e.g. R ¹⁰ may be o-methylphenyl.

According to another aspect of the invention, W may be (R ⁹ )xC (R ⁹ ) _x .c

where Z can be NR, R can be methyl or hydrogen, one of (R ⁹ ) _x can be H and R ⁵ can be H. Alternatively, W can be

where R can be H and R ⁸ is methyl.

The invention is further illustrated by the following examples (including general synthetic schemes), which illustrate various aspects of the invention but do not limit the scope of the invention as defined in the claims.

Examples of embodiments of the invention

Example A

Synthesis of 1-dimethylsulfamoyl-2-t-butyldimethylsilyl-5-imidazolecarboxaldehyde:

1) n-BuLi, -78°C

_{SO2NMe2 ​}

CISO ₂ NMe ₂

Et ₃ N, benzene^

2) TBDMSCI

1) sec-BuLi, -20°C

2) DMF

About TBDMS OHC7~N

_{SO2NMe2 ​}

Procedure

Imidazole (1) (20.0 g, 0.29 mol), triethylamine (41.0 ml, 0.29 mol) and N,N-dimethylsulfamoyl chloride (31.6 ml, 0.29 mol) were added to 320 ml of benzene. The reaction mixture was stirred for 48 hours at room temperature and then filtered. The filtrate was concentrated under reduced pressure. Vacuum distillation of the crude product (-0.5 mmHg, 115-118 degrees Celsius) gave 38.7 g (76%) of a clear and colorless oil. Upon cooling, the product solidified as white crystals (2). 1-(Dimethylsulfamoyl)imidazole (2) (18.8 g, 0.11 mol) was added to 430 ml of tetrahydrofuran (THF). The solution was cooled to -78 degrees Celsius. A solution of n-butyllithium (n-BuLi) in hexane (1.6 M, 70.9 mL, 0.11 mol) was added dropwise to the reaction vessel. After the addition was complete, the reaction mixture was stirred for 1 h at -78 degrees Celsius. t-Butyldimethylsilyl chloride (17.8 g, 0.12 mol) in 50 mL THF was added to the reaction via cannula. After the addition was complete, the reaction mixture was allowed to warm slowly to room temperature and then stirred for 24 h. The reaction mixture was diluted with water and the organic layer was separated. The organic phase was washed with brine and then dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure. Column chromatography (V (eluent 20% ethyl acetate/hexane) gave a pale yellow solid. Recrystallization from pentane gave 30 g (94%) of white crystals (3).

1-Dimethylsulfamoyl-2-t-butyldimethylsilylimidazole (3) (5.0 g, 17.3 mmol) was added to 100 mL of THF. The solution was cooled to -20 degrees Celsius. A solution of sec-butyllithium (s-BuLi) in hexane (1.3 M, 14.6 mL, 19 mmol) was added dropwise to the reaction vessel. After the addition was complete, the reaction mixture was stirred for 1 hour at -20 degrees Celsius. 8 mL of dimethylformamide (DMF) was added to the reaction and then stirred at room temperature for 3.5 hours. The reaction mixture was diluted with water and the organic layer was separated. The organic phase was washed with brine and then dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure. Column chromatography (elution with 20% ethyl acetate/hexane) gave a light yellow oil. Upon cooling, the product solidifies to form yellow crystals of 1-dimethylsulfamoyl-2-t-butyldimethylsilyl-5-imidazolecarboxaldehyde.

Example B-1

Procedure for the preparation of 4(5)-(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1H-imidazole hydrochloride:

40% _HOSO4

90°C

O

Procedure

7-Methoxy-1-tetralone (1) (1.5 g, 8.5 mmol) and 1-dimethylsulfamoyl-2-t-butyldimethylsilyl-5-imidazolecarboxaldehyde (2) (2.7 g, 8.5 mmol) were added to 8.5 ml of 40% sulfuric acid solution. The reaction mixture was then heated for 24 hours at 90 degrees Celsius. After cooling to room temperature, the reaction mixture was basified with an excess of concentrated ammonium chloride solution. The mixture was extracted twice with THF. The organic layers were combined and washed with brine. The organic layer was separated and dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure to

• · ·· ·· ·· ·4 ··· · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· Column chromatography with 7% methanol in chloroform gave 1.05 g (46%) of a brownish solid containing 2-[3Himidazol-4(5)-ylmethyl]-7-methoxy-3,4-dihydro-2H-naphthalen-1-one (4) (B-1a). (4) (0.5 g, 1.95 mmol) was added to 20 mL of methanol. Sodium borohydride (74 mg,

1.95 mmol). After stirring at room temperature for 2.5 hours, the reaction mixture was quenched with water. The reaction mixture was then extracted twice with ethyl acetate. The organic layers were combined and washed with brine. The organic layer was separated and dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure to give 0.5 g of a white solid (5) containing 2-[3H-imidazol-4(5)-ylmethyl]-7-methoxy-3,4-dihydro-2H-naphthalen-1-ol. The crude product was dissolved in 26 mL of dichloromethane. Triethylsilane (2.5 mL, 15.6 mmol) and trifluoroacetic acid (4.8 mL, 62.3 mmol) were added and the reaction mixture was stirred at room temperature for 22 hours. The reaction was then basified with 2 N NaOH and the organic layer was separated and washed with brine. The solution was dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure. Column chromatography with 7% methanol in chloroform gave 0.39 g (83%) of a brownish oil (6). The product was dissolved in methanol and excess HCl in ether was added. The solution was concentrated under reduced pressure to give 0.3 g of a brownish solid. Column chromatography with 7% methanol in chloroform gave 0.25 g (46%) of 4(5)-(7-methoxy-1,2,3,4tetrahydronaphthalen-2-ylmethyl)-1H-imidazole hydrochloride (B-1) as white crystals after recrystallization from acetone and methanol.

• · · · · · · I • · · * ♦; · • · · · · φ •4 · 4 4 4 ·· 44 44 44 ¹ H NMR (300 Mhz, CD ₃ OD) 8.83 (s, 1H), 7.38 (s, 1H), 6.95 (d, 1H, J=8.5 Hz), 6.66 (d, 1H, J=8.4 Hz), 6.57 (s, 1H), 3.73 (s, 3H), 2.71-2.81 (m, 5H), 2.43-2.52 (m, 1H), 1.90-2.14 (m,

2H), 1.40-1.51 (m, 1H).

Following the procedure in Example B-1, various fused-ring compounds are reacted to form the imidazole derivatives listed below.

Example B-2(a-d)

4-chromanone (2a) 3-(3H-imidazol-4(5)-ylmethylene)chroman-4-one (2b) 3-(3H-imidazol-4(5)ylmethyl)chroman-4-one (2c) 3-(3H-imidazol-4(5)ylmethyl)chroman-4-ol (2d) 4(5)-chroman-3-ylmethyl)chroman-4-one (2c)

Example B-3 (a-b)

-tetralone (3a) 2-(3H-imidazol-4(5)ylmethyl)-3,4-dihydro-2Hnaphthalen-1-one (3b) 4(5)-(1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1 Himidazole

Example B-4 (a-b)

4-methyl-1-tetralone (4a) 4(5)-(4-methyl-1,2,3,4-tetrahydronaphthalen-2ylmethyl)-1H-imidazole « « (4b) 2-(3H-imidazol-4(5)-ylmethyl)-4-methyl-3,4-dihydro2H-naphthalen-1-one

Example B-5 (a-b)

Thiochroman (5a) 3-(3H-imidazol-4(5)-ylmethylene)thiochroman-4-one (5b) 3-(3H-imidazol-4(5)-ylmethyl)thiochroman-4-one

Example B-6

The hydrochloric acid salt of the preceding compound is prepared according to step 5 of the method of Example B-1, above.

Thiochroman 4(5)-thiochroman-3-ylmethyl-1H-imidazole

Example B-7 (a-c)

-indanone (7 a) 2-(3H-imidazol-4(5)-ylmethylene)indan-1-one (7b) 2-(3H-imidazol-4(5)-ylmethyl)indan-1-one (7c) 4(5)-indan-2-ylmethyl-1 H -imidazole • · · · · · · · · · · · · · · ·

Example B-8 (a-b)

7-methyl-1-tetralone (8a) 2-(3H-imidazol-4(5)-ylmethyl)-7-methyl-3,4-dihydro2H-naphthalen-1-one (8b) 4(5)-(7-methyl-1,2,3,4-tetrahydronaphthalen-2ylmethyl)-1H-imidazole

The hydrochloric acid salt of this compound was prepared according to the method described in Example B-6.

Example B9 (a-c)

4-keto-4,5,6,7-tetrahydrothianaphthene (9a) 4(5)-(4 ₁ 5 ₁ 6 _I 7-tetrahydrobenzo[b]thiophen-5-ylmethyl)1 H-imidazole

The hydrochloric acid salt of this compound was prepared according to the method described in Example B-6.

(9b) S-ÍSH-imidazoMÍSJ-ylmethylO-eyl-dihydro-SHbenzo[b]thiophen-4-one

The hydrochloric acid salt of this compound was prepared according to the method described in Example B-6.

(9c) 5-(Octahydrobenzo[b]thiophen-5-ylmethyl-1H-imidazole >i· • · ·· ·· · · • · · · • ftft ··· · ftft

Example B-10

4,4-Dimethyl-1-tetralone 4(5)-(4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-2- ylmethyl)-1H-imidazole

Example B-11 (a-b)

1 -Benzosuberone (lla) 4(5)-(6,7,8,9-tetrahydro-5H-benzocycloheptene-6- ylmethyl)-1H-imidazole (llb) 6-(1H-imidazol-4(5)-ylmethylene)-6,7,8,9- tetrahydrobenzocyclohepten-5-one

1 -Benzosuberone (lla) 4(5)-(6,7,8,9-tetrahydro-5H-benzocycloheptene-6- ylmethyl)-1H-imidazole (llb) 6-(1H-imidazol-4(5)-ylmethylene)-6,7,8,9- tetrahydrobenzocyclohepten-5-one Example C-1

Preparation procedure for 4(5)-thiophen-3-ylmethyl-1H-imidazole:

r« V

N

_{SO2NMe2 ​}

1) n-BuLi

2) TBSCI

3) n-BuLi ^4> sa 2

TBAF

CH

//

N

EuSiH

CF,CO,H

_{CH2Cl2 ​}

1ANHC1 reflux

Procedure

1-(Dimethylsulfamoyl)imidazole (1) (2.0 g, 11.4 mmol) was stirred into 42 mL of anhydrous THF and cooled to -78 degrees Celsius. n-BuLi (6.6 mL, 10.6 mmol) was added dropwise to solution (1). The resulting solution was stirred for 30 min at -78 degrees Celsius. tert-butyldimethylsilyl chloride (TBSCI) (1.6 g, 10.6 mmol) in 8 mL of THF was added to the reaction. The reaction mixture was warmed to room temperature and stirred overnight. The next day, the reaction was cooled to -20 degrees Celsius and 7.3 mL (11.6 mmol) of n-BuLi was added. After stirring for 45 min at -20 degrees Celsius, 3-thiophenecarboxaldehyde (2) (1.0 mL, 11.6 mmol) was added to the reaction mixture. The reaction was then warmed to room temperature and stirred overnight. The following day, the reaction was quenched with water and diluted with ethyl acetate. The organic layer was washed with water and then brine. The organic phase was dried over

• · • ·' · ·· »· * ·· · • · • · • • · · • · ·· • · • • · • · · · • · • • · · · ·· ·· • ·

sodium sulfate and the solvent was removed under reduced pressure. Flash chromatography (2:5 ethyl acetate/hexane) gave 3.0 g (7.5 mmol) of 2-(t-butyldimethylsilyl)-5-(hydroxythiophen-2-ylmethyl)imidazole-1-sulfonic acid dimethylamide (3). Compound (3) (1.5 g, 3.74 mmol) was stirred into 37 ml of THF. A 1M solution of tetra-n-butylammonium fluoride (TBAF) in THF (4.1 ml, 4.1 mmol) was added dropwise to the solution (3). The reaction mixture was stirred overnight at room temperature. The next day, the reaction mixture was quenched with water and then extracted with ethyl acetate. The organic layer was washed with water and then with brine. The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. 0.94 g (0.33 mmol) of 5-(hydroxythiophen-2-ylmethyl)imidazole-1-sulfonic acid dimethylamide (4) was obtained. (4) (0.5 g, 1.74 mmol) was stirred into 23 ml of dichloromethane, 2.2 ml (13.9 mmol) of triethylsilane and 4.3 ml (55.7 mmol) of acid were added to the solution. trifluoroacetic acid. The reaction was stirred overnight at room temperature and then quenched with water and neutralized with solid sodium bicarbonate. The organic layer was washed with water and then brine. The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. Flash chromatography using a 1:1 mixture of ethyl acetate and hexane afforded 0.42 g (1.55 mmol) of 5-(thiophen-2-ylmethyl)imidazole-1-sulfonic acid dimethylamide (5). (5) (0.42 g, 1.55 mmol) was stirred into 10 mL of 1.5 N HCl and the mixture was heated to reflux for 3 h and then stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, neutralized with solid sodium bicarbonate and then basified with 2 N NaOH. The organic layer was washed with water and then brine. solution. The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. Flash chromatography using a 10:1 mixture of chloroform and methanol gave 0.17 g (1.0 mmol) of 4(5)-thiophen-3ylmethyl-1H-imidazole (6) (C-1).

• φφ φφ ·· φφ • φφφφ φφφφ • φ φφφφ φφφφ • φφφφφ φ· φφφ Φφφ φ φφφφ φφφφ φφφ φφ φφ φφ ¹ Η NMR (300 MHz, CD ₃ OD) 7.52 (s, 1Η), 7.25-7.27 (m, 1Η), 6.96-7.01 (m, 2Η), 6.77 (s,

1H), 3.98 (s, 2H).

Example C-2

The 2-carboxaldehyde isomer of 3-thiophenecarboxaldehyde is substituted according to the method outlined in Example C-1 to give 4(5)-thiophen-2-ylmethyl-1H-imidazole.

Example C-3

5-Methyl-2-thiophenecarboxaldehyde is substituted with 3-thiophenecarboxaldehyde according to the method outlined in Example C-1 to give 4(5)-(5-methylthiophen-2-ylmethyl)-1H-imidazole.

Example C-4

5-Chloro-2-thiophenecarboxaldehyde of 3-thiophenecarboxaldehyde is substituted according to the method set forth in Example C-1 to give 4(5)-(5-chlorothiophen-2-ylmethyl)-1H-imidazole.

Example C-5

2-Furancarboxaldehyde is substituted according to the method outlined in Example C-1 to give 4(5)-furan-2-ylmethyl-1H-imidazole.

♦ · ·♦ ·· 4 • 4 4 4 4 4 4 4 4 • · · · · · · 4 9

Example C-6

3-Furancarboxaldehyde is substituted according to the method outlined in Example C-1 to give 4(5)-furan-3-ylmethyl-1H-imidazole.

Example C-7

5-Methyl-2-furancarboxaldehyde is substituted according to the method outlined in Example C-1 to give 4(5)-(5-methylfuran-2-ylmethyl)-1H-imidazole.

Example C-8

Benzaldehyde is substituted according to the method set forth in Example C-1 to give 4(5)-benzyl-1H-imidazole.

Example C-9

2-Thianaphthenecarboxaldehyde is substituted according to the method outlined in Example 01 to give 4(5)-benzo[b]thiophen-2-ylmethyl-1H-imidazole.

Example C-10

2-Benzofurancarboxaldehyde is substituted according to the method given in Example

C-1 to give 4(5)-benzofuran-2-ylmethyl-1H-imidazole.

* tt tt 9 tt tttt tttt • tttt tt • « ·· • · · · • · · · ttt tttt •tt tttt • · · I • · · 1 • · · <

• ttttt 4 • tt tttt

Example C-11

5-Ethyl-2-furancarboxaldehyde is substituted according to the method outlined in Example C-1 to give 4(5)-(5-ethylfuran-2-ylmethyl)-1H-imidazole.

Example C-12

4-Bromo-2-thiophenecarboxaldehyde is substituted according to the method outlined in Example C-1 to give 4(5)-(4-bromothiophen-2-ylmethyl)-1H-imidazole.

Example C-13

4-Phenyl-2-thiophenecarboxaldehyde is substituted according to the method outlined in Example C-1 to give 4(5)-(4-phenylthiophen-2-ylmethyl)-1H-imidazole.

Example C-14

4-Methyl-2-thiophenecarboxaldehyde is substituted according to the method set forth in Example C-1 to give 4(5)-(4-methylthiophen-2-ylmethyl)-1H-imidazole hydrochloride.

Example D-1

Preparation procedure for oxazolidin-2-ylidene-(3-phenylbicyclo[2.2.1]hept-2-yl)amine:

*β·

99 99 88 88

8 8 9 9 « · · <

• · ···« · · · 4

8998 88 89 9 9 9 89 fl • 9 9 9 8 9 9 8 i

98 88 98 98

O CH ₃ NO ₂ / KOH / MeOH OH W'H ~~

HCI

C ₆ H _S ^ ^NO * cich ₂ ch ₂ ci

C _fi H

6 ⁿ 5

NO,

_H2 /Pd-C

NH,

1) chloroisocyphiate

2) NaHCO ₃ \ ?6H _S

Λ7

HN^

Procedure

As shown above, the endo exo relative stereochemical compositions of the given compound, namely beta-nitrostyrene, were prepared. Reaction of a methanol solution of benzaldehyde (10 g, 94.3 mmol) with nitromethane (51 mL, 943 mmol) in the presence of sodium hydroxide (3 N in methanol, pH=8) gave the nitroalcohol in 60% yield. Dehydration of the alcohol was carried out with methanesulfonyl chloride (3.56 g, 31.1 mmol) followed by triethylamine (6.3 g, 62.2 mmol) in dichloromethane (35 mL) to give the product in 97% yield. Kugelrohr distillation was used to purify the compound. The construction of the bicyclo[2.2.1]heptane skeleton was carried out in a single step. The Diels-Alder reaction is carried out by heating nitrostyrene (4.5 g, 30.2 mmol) with cyclopentadiene (3.98 g, 60.4 mmol) in 1,2-dichloroethane (10 ml). The Diels-Alder reaction proceeds in an approximately 3:1 endo:exo ratio. The ratio and relative stereochemistry can be demonstrated by X-ray analysis. Reduction of both the nitro group and the olefin is carried out under a hydrogen atmosphere in the presence of 10 wt% palladium on activated carbon. The isomers are easily separated at this stage by flash chromatography using methanol saturated with 5% ammonia in dichloromethane. The amine (0.7 g, 3.74 mmol) was first treated with chloroethyl isocyanate (0.38 mL, 4.49 mmol) to form chloroethyl urea, which was then heated in the presence of aqueous NaHCO ₃ to afford oxazolidin-2-ylidene-(3-phenylbicyclo[2.2.1]hept-2-yl)amine (D-1) in 51% yield.

¹ H NMR (300 MHz, CDCl ₃ ) d 1.36-1.80 (m, 6H), 2.14 (d, 1H, J=4.40 Hz), 2.37 (s, 1H), 2.65 (s, 1H), 3.71-3.78 (m, 2H), 3.95-3.98 (m, 1H), 4.19-4.25 (t, 2H, J=17.15 Hz, J=8.36 Hz), 7.17-7.29 (m, 5H).

Example D-2

Oxazolidin-2-ylidene-(3-o-tolylbicyclo[2.2.1]hept-2-yl)amine was prepared by substitution of omethyl-beta-nitrostyrene according to the method set forth in Example D-1.

Example D-3

Bicyclo[2.2.1]hept-2-yl oxazolidin-2-ylideneamine was prepared by nitrothene substitution according to the method outlined in Example D-1.

Example E-1

Procedure for the preparation of imidazolidin-2-ylidene-(4-methyl-3,4-dihydro-2H-benzo(1,4]oxazin-6-yl)amine:

X, ν' • · • · • · ·

Cl

THF / reflux / 24h

1) HCHO/NaBH ₃ CN

2) AcOH reflux ·· ·«

Pd-C/H ₂ THF/ MeOH (1:1)

r~\ hn^n sat ₃ h

2 ^C o W ^3N

Procedure

To a mixture of 2-amino-4-nitrophenol (1) (4.00 g, 25.95 mmol), triethylamine (15.20 mL, 109.0 mmol), and 4-dimethylaminopyridine (0.063 g, 0.52 mmol) in anhydrous CH2Cl2 (250 mL) at 0 degrees Celsius under argon was added chloroacetyl chloride (2.27 mL, 28.55 mmol) via syringe. After refluxing for 72 hours, the pure product was filtered off and washed with water. The original liquid was then washed with phosphoric acid (0.5 M), saturated sodium bicarbonate solution, water, and brine, and dried over MgSO4. This solution was adsorbed onto silica gel and purified by flash chromatography with hexane/ethyl acetate (4:6) to give additional product. The combined solids were dried in vacuo to give pure 6-nitro-4H-benzo[1,4]oxazin-3-one (2) (4.12 g) in 82% yield. Borane dimethyl sulfide complex (15.3 mL, 30.62 mmol) was added to a slurry of (2) (1.49 g, 7.65 mmol) in anhydrous THF (40 mL) under argon in a two-necked round-bottomed flask equipped with a reflux condenser. The mixture was heated under reflux until the starting material could no longer be detected by thin layer chromatography (2 hours). The reaction mixture was cooled to room temperature and methanol was carefully added dropwise. The resulting mixture was then heated under reflux for an additional 10 minutes. The crude reaction mixture was concentrated in vacuo and purified by flash chromatography on silica gel with hexane/ethyl acetate (8:2) to give pure 6-nitro-3,4-dihydro-2H-benzo[1,4]oxazine (3) (1.36 g) as an orange solid in 99% yield. To (3) (0.032 g, 0.178 mmol) and formalin (37% in H2O, 0.20 mL, 2.67 mmol) in anhydrous acetonitrile (1.5 mL) at room temperature was added sodium cyanoborohydride (0.034 g, 0.534 mmol). This solution was stirred for 30 min, then glacial acetic acid (0.032 mL, 0.534 mmol) was added. The resulting mixture was stirred for an additional 16 h. The organics were separated in diethyl ether and washed successively with NaOH (2 N) and brine, dried over MgSO4, and concentrated in vacuo. The resulting solids were purified by flash chromatography on silica gel with hexane/ethyl acetate (7:3) to give pure 4-methyl-6-nitro-3,4-dihydro-2Hbenzo[1,4]oxazine (4) (0.031 g) in 91% yield. To (4) (2.16 g, 11.12 mmol) and 10% palladium on carbon (0.216 g, 10% wt) under argon was added methanol (MeOH) (30 mL) followed by THF (30 mL). Hydrogen was bubbled through the resulting slurry until no trace of (4) was detected by thin layer chromatography (2 h). Celite was added and the mixture was filtered through a pad of Celite, followed by washing with ·· « · · · · · · * • · · · · · · · · · · ·

MeOH. The resulting solution was concentrated in vacuo to give pure 4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylamine (5) (1.86 g) as a pale purple oil in 100% yield, which was obtained without further purification. To compound (5) (1.86 g, 11.34 mmol) and imidazoline-2-sulfonic acid (1.84 g, 12.24 mmol) in anhydrous acetonitrile (50 mL) under argon at 0 degrees Celsius was added triethylamine (3.26 mL, 23.36 mmol). This solution was gradually warmed to room temperature and stirred for 16 hours. During this time, additional imidazoline-2-sulfonic acid (0.86 g, 5.55 mmol) was added and the resulting mixture was stirred for an additional 5 hours. The solution was concentrated in vacuo and the residue was taken up in H2O. The organics were extracted into CH2Cl2 and washed twice with NaOH and brine, dried over _MgSO4 and concentrated in vacuo. The resulting foam was purified by flash chromatography on silica gel with 20% methanol (saturated with ammonia) in chloroform to give pure imidazolidin-2-ylidene-(4-methyl3,4-dihydro-2H-benzo[1,4]oxazin-6-ylamine (6) (E-1) (0.905 g) in 34% yield.

¹ H NMR (CDCb): 2.81 (s, 3H), 3.26 (t, J=8.9 Hz, 2H), 3.60 (s, 4H), 4.26 (m, 2H), 4.60 (vbrs, 2H), 6.34 (dd, J=8.2 Hz, J=2.4 Hz, 1H), 6.39 (d, J=2.4 Hz, 1H), 6.68 (d, J=8.2 Hz, 1H).

Examples F and G

Procedure for the preparation of 6-(imidazolidin-2-ylideneamino)-5-methyl-4H-benzo[1,4]oxazin-3-one (F) and imidazolidin-2-ylidene-5-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)amine (G):

·«>’ tt • ·

₂

Oh

2)

C,-V ^CI

Pd-C (10%) / h ₂

THF-MeOH (1:1)

' 6

EfcN (2.5 e-Uy.) CH ₃ CN / reflux 80h

Γ~\

NyNH

SO3H (3.6 mlcv.^

Procedure

To 2-amino-3-methylphenol (1) (14.72 g, 0.12 mol), triethylamine (35.0 mL, 0.251 mol) and dimethylaminopyridine (0.29 g, 2.39 mmol) in anhydrous CH ₂ Cl ₂ (100 mL) at 0 degrees Celsius under argon was added dropwise via syringe « ···· · · · · · · · · · · · · · · · · · · «·· · · · · · · ·. «· chloroacetyl chloride (10.0 mL, 0.126 mol). After addition was complete, the resulting solution was heated under reflux for 24 h. The organics were washed successively with phosphoric acid (0.5 M), saturated sodium bicarbonate solution, water and brine and then dried over MgSO 4 . The resulting solution was concentrated and partitioned into THF to which ether was added. The resulting crystals were filtered to give pure 5-methyl-4Hbenzo[1,4]oxazin-3-one (2) (12.30 g) in 63% yield. To (2) (14.64 g, 89.72 mmol), dissolved in concentrated H2SO4 (65 mL), was added 70% HNO3 (8.08 g, 89.72 mmol) in concentrated H2SO4 (25 mL) at -10 degrees Celsius with rapid mechanical stirring at a rate that kept the internal temperature below -5 degrees Celsius. Immediately after the addition was complete, the mixture was poured onto crushed ice (500 mL) and the resulting solids were filtered off and stirred in cold water (300 mL) to form a slurry, with sufficient NaOH added to adjust the pH to 7. The resulting yellow powder was dissolved in THF, adsorbed onto silica gel and purified by flash chromatography with 60% hexane/ethyl acetate to give the nitro product as a mixture of two regioisomers, i.e. the desired 6-substituted aromatic containing 6nitro-5-methyl-4H-benzo[1,4]oxazin-3-one (3) (55%) and the 8-substituted by-product containing 8-nitro-5-methyl-4H-benzo[1,4]oxazin-3-one (4) (22%). These isomers were difficult to isolate at this point and were therefore carried forward as a mixture. To a mixture of compounds (3) (1.93 g, 9.27 mmol) and (4) (0.48 g, 2.32 mmol) dissolved in a solution of MeOH (300 mL) and THF (300 mL) under argon was added 10% palladium on carbon (1.20 g). The resulting solution was then exposed to H ₂ at atmospheric pressure. After 16 h, the catalyst was filtered off and the resulting solution was concentrated in vacuo and purified by flash chromatography on silica gel with 50% hexane and ethyl acetate to give 6-amino-5-methyl-4H-benzo[1,4]oxazin-3-one (5) (0.96 g) in 46% yield and 8-amino-5-methyl-4H-benzo[1,4]oxazin-3-one (6) (0.17 g) in 8% yield. (5) (1.20 g, 6.74 · .· ·'· ·» ·· · ·' ·· * · · · · « · · * • · · · · ·· · · · «.

• ···· · » · ··· · « · • · · · · · · » · ·· · ·» · ·» «· mmol), imidazoline-2-sulfonic acid (2.02 g, 13.48 mmol) and triethylamine (2.35 ml, 16.85 mmol) were heated under reflux in anhydrous acetonitrile (50 ml) under argon for 48 h. Then, additional imidazoline-2-sulfonic acid (1.01 g, 6.74 mmol) and triethylamine (1.41 ml, 10.12 mmol) were added and the resulting mixture was stirred for another 24 h. The solution was concentrated in vacuo and the residue was dissolved in CHCl3/isopropanol (3:1) and subsequently washed with NaOH (1N) and brine, dried over MgSO4 and concentrated in vacuo. The resulting foam was purified by flash chromatography on silica gel using 20% methanol saturated with ammonia in chloroform to give 6-(imidazolidin-2-ylideneamino)-5-methyl4H-benzo[1,4]oxazin-3-one (7) (0.42 g) as a foam in 27% yield along with 55% recycled starting material. The hydrochloric acid salt was recrystallized from ethanol/diethyl ether (ΕίΟΗΖΕί ₂ Ο) to give fine white needles.

Η NMR (DMSO): 2.10 (s, 3H); 3.59 (s, 4H); 4.53 (s, 2H); 6.83 (d, J=8.6 Hz, 1H); 6.90 (d,

J-8.6 Hz, 1H); 8.07 (brs, 2H); 1015 (vbrs, 1H); 10.42 (s, 1H).

Compound (6) (0.222 g, 1.35 mmol), imidazoline-2-sulfonic acid (0.223 g, 1.49 mmol) and triethylamine (0.415 mL, 2.98 mmol) were heated at 95 degrees Celsius in anhydrous acetonitrile (10 mL) in a sealed tube for 2 hours. Additional imidazoline-2-sulfonic acid (0.112 g, 0.75 mmol) was then added and the reaction was allowed to proceed for an additional 16 hours.

The solution was concentrated in vacuo and the residue was dissolved in CHCl3:isopropyl alcohol (3:1) and washed with NaOH (2N) and brine, dried (MgSO4) and concentrated in vacuo. The resulting oil was recrystallized from CHCl3 to give pure 6-(imidazolidin-2ylideneamino)-5-methyl-4H-benzo[1,4]oxazin-3-one (8) (F) (0.048 g) as a white powder in 15% yield along with 35% recycled starting material. To the slurry of

0(:

(8) (0.08g, 0.321 mmol) in anhydrous THF (50 mL) under argon in a 3-neck round-bottomed flask equipped with a reflux condenser was added with borane-dimethylsulfide complex (0.48 mL, 0.936 mmol). The mixture was heated under reflux until the starting material was no longer detectable by thin layer chromatography (3 hours). The reaction mixture was cooled to room temperature and carefully quenched with methanol added dropwise. The crude reaction mixture was concentrated in vacuo and purified by flash chromatography on silica gel using 20% methanol saturated with ammonia/chloroform to afford imidazolidin-2-ylidene-(5-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)amine (9) (G) (0.03 g) as the HCl salt in 37% yield.

H NMR (CDCl ₃ ): 2.07 (s, 3H); 3.46 (t, J=4.3 Hz, 2H); 3.55 (s, 4H); 4.24 (t, J=4.3 Hz, 2H);

5.60 to 5.95 (vbrs, 2H); 6.44 (d, J=8.0 Hz, 1H); 6.57(d, J=8.0 Hz, 1H).

Example H

Preparation procedure for 4(5)-phenylsulfanyl-1H-imidazole:

_{SO2NMe2 +}

If

SO ₂ NMe ₂

TBAF

_{SO2NMe2 ​}

S. ν HCl

Procedure 1-(N,N-Cimethylsulfamoyl)imidazole (1.5 g, 8.6 mmol) was dissolved in 28 mL THF. The solution was cooled to -78 degrees Celsius and n-BuLi (5.4 mL, 5.6 mmol) was added dropwise via cannula. After stirring at -78 degrees Celsius for 1 h, TBSCI (1.3 g, 8.65 mmol) in 10 mL THF was added. The bath was removed and the reaction mixture was allowed to warm to room temperature. The reaction mixture was then stirred overnight. The reaction mixture was cooled to -20 degrees Celsius and n-BuLi (5.4 mL, 8.6 mmol) was added. After 45 min, phenyl disulfide (1.9 g, 8.6 mmol) in 8 mL THF was added. The reaction mixture was stirred at room temperature for 48 h. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic solvent layer was separated and washed with water and then brine. The organic layer was collected and washed with water and then brine. The solution was dried over sodium sulfate and the solvent was removed under reduced pressure. Flash chromatography (2.5% EtOAc/hexane) gave 2.8 g (7.0 mmol) of 2-(t-butyldimethylsilyl)-5-phenylsulfanylimidazole-1-sulfonic acid dimethylamide (1) as a yellow oil. Compound (1) (2.8 g, 7.0 mmol) was dissolved in THF and the solution was cooled to 0 degrees Celsius. TBAF (7.0 mL, 7.0 mmol) was added dropwise to the solution. The reaction mixture was stirred overnight at room temperature. The next day, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with water and then brine. The solution was dried over sodium sulfate and the solvent was removed under reduced pressure. Flash chromatography (50% EtOAc/hexane) gave 474 mg of 5-phenylsulfanilimidazole-1-sulfonic acid dimethylamide (2) and 290 mg of 5-phenylsulfanyl1H-imidazole (3) (H). 478 mg of compound (2) was added to 2N HCl and the solution was heated under reflux for 2 hours. The reaction mixture was basified with 2N NaOH and extracted with ethyl acetate. The organic solvent layer was washed with water and then with brine. The solution was dried over sodium sulfate and the solvent was removed under reduced pressure. Flash chromatography (EtOAc) gave compound (3) as a white crystalline solid. Mixing gave a total of 360 mg (2.0 mmol) of compound (3).

¹ H NMR (300 MHz, CD ₃ OD): 7.91 (s, 1H), 7.37 (s, 1H), 7.19-7.23 (m, 2H), 7.07-7.11 (m,

3H).

Example I

Preparation procedure of 4(5)-(1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-4,5-dihydro-1 H-imidazole methanesulfonate:

O

BH ₃ -Me ₂ S

HIM'

1) Example: imidazole

THF/20°C

2) l ₂ / benzene.

THF/Cul „ -78 C to 25°C

24h / 70°C

NaN ₃ / acetone-F^O

Procedure

To 1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (1) (4.93 g, 27.42 mmol) in anhydrous THF (250 ml) at 20 degrees Celsius under argon was added 3.26 ml (32.90 mmol) of borane-dimethylsulfide (BH3-Me ₂ S) via cannula. After stirring for 16 hours, MeOH (4 ml) was added and the mixture was heated to 55 degrees Celsius until no further gas evolution occurred. The mixture was concentrated to an oil, dissolved in Et ₂ O, and then washed with 2 M acid • '· tt· ♦ · tttt ·· tt ¹ · · · tt'»' tt 'ti .tttt ♦ tt tt · · ttttt .» -tt tt «.

• ···· · tt » · tt 'tt- tt ’·- tt · tt · ttttt· ttttt· «·'·.' . · ·· ·· tttt tttt phosphoric acid, saturated sodium bicarbonate solution, water and brine and then dried over MgSO4 and concentrated again. The resulting oily substance was purified under high vacuum (Kugelrohr distillation) at 150 degrees Celsius to give pure alcohol (1,2,3,4-tetrahydronaphthalen-2-yl)methanol (2) (4.09 g) in 93% yield. To triphenylphosphine (10.179 g, 38.809 mmol) and imidazole (2.64 g, 38.809 mmol) in anhydrous benzene (75 mL) was added iodine (8.06 g, 33.865 mmol) in benzene (75 mL) with rapid stirring, followed by compound (2) in benzene (50 mL). After 3 h, the solids were filtered off and the filtrate was reduced to 50 mL in vacuo. Hexane (200 mL) was then added. The resulting solids were filtered off and the filtrate was subsequently washed with water and brine, dried over MgSO4, and concentrated in vacuo. The resulting oil was purified by flash chromatography on silica gel with hexane to give pure 2-iodomethyl-1,2,3,4-tetrahydronaphthalene (3) (6.239 g) in 90% yield. To compound (3) (10.02 g, 36.85 mmol) and Cul (1.41 g, 7.37 mmol) in anhydrous THF (50 mL) at -78 degrees Celsius under argon was added vinylmagnesium bromide (1M in THF, 73.70 mL, 73.70 mmol) slowly so as to avoid coloration. This solution was allowed to warm to 0 degrees Celsius and stirred for 6 hours. The resulting mixture was recooled to -40 degrees Celsius and carefully quenched with 2 M phosphoric acid (35 mL). This solution was diluted with 100 mL of water and extracted with hexanes. The organic fractions were then washed with water and brine, dried over MgSO4 and concentrated in vacuo. The resulting oil was purified by flash chromatography on silica gel with hexane to give 2-allyl-1,2,3,4-tetrahydronaphthalene (4) (5.618 g) in 88% yield. Compound (4) (5.615 g, 32.645 mmol) and meta-chloroperbenzoic acid (m-CPBA) (14.08 g, 81.613 mmol) were stirred in anhydrous methylene chloride (50 mL) for 16 h. The solids were filtered off and potassium fluoride KF (5.11 g, 88.142 mmol) was added and the mixture was stirred for another hour.

The solids were filtered off and the reaction was concentrated in vacuo. The resulting oil was purified by ^flash chromatography on silica gel with 5% ethyl acetate in hexane to give 2-(1,2,3,4-tetrahydronaphthalen-2-ylmethyl)oxirane (5) (5.41 g) in 88% yield. Sodium azide (1.97 g, 30.271 mmol) was added to a solution of (5) (1.626 g, 8.649 mmol) in acetone (20 mL) and water (5 mL). This solution was heated to 85 degrees Celsius and stirred for 48 hours. The solution was concentrated in vacuo and the residue was dissolved in CHCl ₃ and then washed with water and brine, dried over MgSO 4 and concentrated in vacuo. The resulting oil was purified by flash chromatography on silica gel with 30% ethyl acetate in hexane to give pure 1-azido-3(1,2,3,4-tetrahydronaphthalen-2-yl)propan-2-ol (6) (1.762 g) in 88% yield. A mixture of compound (6) (1.88 g, 8.140 mmol), triphenylphosphine (2.67 g, 10.173 mmol), phthalimide (1.50 g, 10.173 mmol), diethyl azodicarboxylate (DEAD) (1.77 g, 10.173 mmol) was stirred in anhydrous THF (50 mL) for 4 h. This solution was concentrated in vacuo, dissolved in a solution of hexane (25 mL) and ether (25 mL) and stirred for 16 h. The solids were filtered off and the filtrate was concentrated in vacuo. The resulting oil was purified by flash chromatography on silica gel with 20% ethyl acetate in hexane to give 2-[1-azidomethyl 1-2-(1,2,3,4-tetrahydronaphthalen-2yl)ethyl]isoindole-1,3-dione (7) (2.487 g) contaminated with a small amount of impurities that were not removed by further purification. A mixture of compound (7) (3.93 g, 10.917 mmol) and hydrazine (0.680 mL, 21.833 mmol) was heated in ethanol (60 mL) under reflux for 16 h. The solids were filtered off and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel with 5% MeOH in CH ₂ Cl ₂ to give 1-azidomethyl-2-(1,2,3,4-tetrahydronaphthalen-2-yl)ethylamine (8) (2.057 g) in 88% yield.

A mixture of (8) (2.056 g, 8.940 mmol) and 10% palladium on carbon (0.260 g) was stirred in MeOH (30 mL) under hydrogen at 101.33 kPa (1 atm) for 16 h. The solids were filtered off and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel with 10% MeOH saturated with ammonia in CH2Cl2 to give 3-(1,2,3,4-tetrahydronaphthalen-2-yl)propane-1,2-dione (9) (1.557 g) in 85% yield. A mixture of compound (9) (0.590 g, 2.892 mmol) and methanesulfonic acid (0.980 mL, 14.460 mmol) was heated in triethyl orthoformate (10 mL) at 105 °C for 3 h. The reaction mixture was concentrated in vacuo and the solids were filtered off. Subsequent recrystallization of these solids from MeOH/ether afforded pure 4(5)-(1,2,3,4-tetrahydronaphthalen-2ylmethyl)4,5-dihydro-1H-imidazole methanesulfonate (I) (0.435 g) in 48% yield.

¹ H NMR (CDCb): 1.37 to 1.56 (m, 1H), 1.56 to 1.70 (m, 1H), 1.80 to 2.02 (m, 2H), 2.32 to 2.55 (m, 2H), 2.72 to 2.95 (m, 3H), 3.48 to 3.59 (m, 1H), 3.93 to 4.08 (m, 1H), 4.31 to 4.47 (m, 1H), 7.00 to 7.20 (m, 4H), 8.46 (s, 1H), 10.04 (s, 1H), 10.35 (brs, 1H).

Example J-1

Preparation procedure for 4(5)-cyclohexylmethyl-1H-imidazole:

rt SAtbs SO ₂ NMe ₂ 1 1) n-BuLi SO ₂ NMe _{2 Λ} ' ² TBAF oasis™ 3 ^2, cc SO?NMe? H cn \ N reflux N 4 5

Procedure

2-Tert-butyldimethylsilyl-1-dimethylsulfamoylimidazole (1) (4.1 g, 14.2 mmol) was dissolved in 47 mL of anhydrous THF and cooled to -20 degrees Celsius. n-BuLi (8.9 mL,

4 ','4 '4 ·, « '4 · ·

Φ 4> Φ · ΦΦ '· I Φ • Φ···· ’4 *4 4 · « <4 ‘4 · · «44 Φ 4 4 ‘4 4 4 ««· · 4 4 4'· 4' · ··

14.2 mmol) was added dropwise to solution (1). The resulting solution was stirred for 45 min at -20 degrees Celsius. Cyclohexylmethyl iodide (2) (3.14 g, 14 mmol) was then added dropwise to the reaction mixture. The reaction mixture was then warmed to room temperature and stirred overnight. The following day, the reaction was quenched with saturated ammonium chloride solution and diluted with water. The mixture was extracted with ethyl acetate (3 x 100 mL). The organic layers were combined and washed with water and then brine. The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. Flash chromatography (4:1 ethyl acetate/hexane) gave 2.26 g (5.6 mmol) of 5-cyclohexylmethyl-2-tert-butyldimethylsilyl-1-dimethylsulfamoylimidazole (3). Compound (3) (2.26 g, 5.6 mmol) was dissolved in 56 mL of THF and cooled to 0 °C. A 1M solution of TBAF (5.6 mL, 5.6 mmol) was added dropwise to solution (3). The reaction mixture was warmed to room temperature and stirred overnight. The next day, the reaction was quenched with water and then extracted with ethyl acetate. The organic layer was washed with water and then brine. The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. Flash chromatography (1:1 ethyl acetate/hexane) afforded 1.2 g (4.42 mmol) of 5-cyclohexylmethyl-1-dimethylsulfamoylimidazole (4). Compound (4) (1.2 g, 4.42 mmol) was dissolved in 25 mL of 1.5 N HCl solution and refluxed for 2 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The pH of the mixture was adjusted to 13 with 2 N NaOH and then extracted with chloroform (4 x 100 mL). The organic layers were combined and washed with water and then brine. The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. Flash chromatography (9:1 chloroform/methanol) afforded 700 mg (4.27 mmol) of 4(5)-cyclohexylmethyl-1H-imidazole (5) (J-1).

¹ H NMR (CDCl ₃ ): 0.92 to 1.0 (m, 2H), 1.16 to 1.26 (m, 3H), 1.57 to 1.73 (m, 6H), 2.48 (d,

J=6.9 Hz, 2H), 6.77 (s, 1H), 7.56 (s, 1H).

4'4' • 4 ·· |· ·'· · · » 9 · *4 .4 · 4 4'

4 4 44 ·4 · 4 4 4

4 4 4 4 4

Example J-2 (S)-2-iodomethyl-1,2,3,4-tetrahydronaphthalene is substituted according to the method described in Example J-1 to give (S)-4(5)-(1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1H-imidazole. (S)-2iodomethyl-1,2,3,4-tetrahydronaphthalene is prepared from (S)-1,2,3,4-tetrahydro-2-naphthoic acid. (S)-1,2,3,4-tetrahydronaphthoic acid is prepared by melting 1,2,3,4-tetrahydronaphthoic acid (J. Med. Chem. 1983, 26, 328-334).

Example J-3 (R)-2-iodomethyl-1,2,3,4-tetrahydronaphthalene is substituted according to the method described in Example J-1 to give (R)-4(5)-(1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1H-imidazole. (R)-2-iodomethyl-1,2,3,4-tetrahydronaphthalene is prepared from (R)-1,2,3,4-tetrahydro-2-naphthoic acid. (R)-1,2,3,4-tetrahydronaphthoic acid is prepared by melting 1,2,3,4-tetrahydronaphthoic acid (J. Med. Chem. 1983, 26, 328-334).

Example K-1

Preparation procedure for 4(5)-(4,5,6,7-tetrahydrobenzo[b]thiophen-2-ylmethyl)-1H-imidazole:

• · • ·' »· ·· ·· ··« · • * * «ί • · • • • .» • Φ • • • • • • · • · • · • • ·· · • • » • · ··

1) n-BuLi

2)

OHC [| y-TBDMS SO ₂ NMe ₂

TBDMS

_{SO2NMe2 ​}

Procedure

4,5,6,7-Tetrahydrobenzo[b]thiophene (1) (2.1 g, 15 mmol) was dissolved in 75 mL of anhydrous THF and cooled to -78 °C. n-BuLi (6.0 mL, 15 mmol) was added dropwise to solution (1). The resulting solution was stirred for 60 min at -78 °C. 1-Dimethylsulfamoyl-2-t-butyldimethylsilyl-5-imidazolecarboxaldehyde (2) (4.8 g, 15 mmol) in 25 mL of THF was added to the reaction. The reaction mixture was warmed to room temperature and stirred for 2 h before being quenched with water and diluted with ethyl acetate. The organic layer was washed with water and then brine. The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. By flash chromatography (1:3 ethyl acetate/hexane) • · »· *« *· »· ♦ ♦ · · ♦ · · » · · · • · » « · o · · · · » ·«···« 9 9 « «9 9 · · 9

9 9 9 9 9 9 9 9 9

9 9 9 9 9.9 99 ·* 5.2 g (11 mmol) of 2-(tert-butyldimethylsilyl)-5-[hydroxy(4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)methyl]imidazole-1-sulfonic acid dimethylamide (3) was obtained. Compound (3) (5.2 g, 11.3 mmol) was dissolved in 57 mL of THF. A 1 M solution of tetra-n-butylammonium fluoride (TBAF) in THF (11.3 mL, 11.3 mmol) was added dropwise to solution (3). The reaction mixture was stirred for 1 h 15 min before being quenched with water and then extracted with ethyl acetate. The organic layer was washed with water and then with brine. The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. Recrystallization from hexane/ethyl acetate gave 5-[hydroxy-(4,5,6,7tetrahydrobenzo(b]thiophen-2-yl)methyl]imidazole-1-sulfonic acid dimethylamide (4) (2.1 g, 6.2 mmol). Another 2 g of crude product were also obtained. Compound (4) (2.0 g, 5.9 mmol) was dissolved in 78 mL of dichloromethane, and 7.5 mL (46.9 mmol) of triethylsilane and 14.4 mL (0.19 mol) of trifluoroacetic acid were added. The reaction mixture was stirred overnight at room temperature and then quenched with water and neutralized with 2 N NaOH. The organic layer was washed with water and then brine. The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. Flash chromatography using 1:1 ethyl acetate:hexane gave 0.75 g. (2.3 mmol) of 5-(4,5,6,7-tetrahydrobenzo[b]thiophen-2-ylmethyl)imidazole-1-sulfonic acid dimethylamide (5).

Compound (5) (0.42 g, 1.55 mmol) was dissolved in 15 mL of 1.5 N HCl solution and heated under reflux for 2 h and then stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and neutralized with 2 N NaOH. The organic layer was washed with water and then brine. The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. The crude product was dissolved in methanol and excess HCl in ether was added. The solvent was removed under reduced pressure to give 0.6 g (2.3 mmol) of 4(5)-(4,5,6,7-tetrahydrobenzo[Ib]thiophen-2-ylmethyl)imidazole (6) (K-1).

φ '» ·φ φφ φφ φφ • Φ φ φφφ» φφφφ φφ φ φφφφ φφφφ φ φφφφ φ ♦ φ φ 'φφφ · φ φ φ φφφφ φφφφ φφφ ¹ Η NMR (CD ₃ OD): 8.80 (s, 1Η), 7.34 (s, 1Η), 6.57 (s, 1Η). 4.18 (s, 2Η), 2.65 to 2.69 (m, 2H), 2.51 to 2.55 (m, 2H), 1.74 to 1.83 (m, 4H).

Example K-2

2-(Tert-butyl)furan is substituted according to the method outlined in Example K-1 to give 4(5)-(5-tert-butylfuran-2-ylmethyl)-1H-imidazole.

Example K-3

5,6-Dihydro-4H-thieno[2.3-b]thiopyran is substituted according to the method outlined in Example K-1 to give 4(5)-(5,6-dihydro-4H-thieno[2.3-b]thiopyran-2-ylmethyl)-1H-imidazole.

Example L

Preparation procedure for 4(5)-(1-furan-2ylethyl)-1H-imidazole:

• * 99 99 • 9 99 • 9 · • 9' • 9 9 9 9 9 9 · • • 9 • 9 9 9 9 « 9 9 9 9 • 9 9 9 • « 999 9 9« 99 99 99

AND

_{SO2NMe2 ​}

1) n-BuLi

TBAF

_Et3SiH

_{CF3CO2H ​}

_{Cr2Cl2 ​}

MeMgCl

1.5NHC1 reflux

Procedure

2-(Tert-butyldimethylsilyl)-1-(dimethylsulfamoyl)imidazole (1) (3.3 g, 11.4 mmol) was dissolved in 38 mL of anhydrous THF and cooled to −78 °C. n-BuLi (7.2 mL, 11.4 mmol) was added dropwise to solution (1). The resulting solution was stirred for 30 min at −78 °C. 2-Furfural (2) (0.94 mL, 11.4 mmol) was added to the reaction. The reaction mixture was warmed to room temperature and stirred overnight. The following day, the reaction was quenched with saturated ammonium chloride solution and diluted with ethyl acetate. The organic layer was washed with water and then brine. The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. Flash chromatography (4:1 ethyl acetate/hexane) gave 4.4 g (11.4 mmol) of 2-(t-butyldimethylsilyl)-5-(furan-2-ylhydroxymethyl)imidazole-1-sulfonic acid dimethylamide (3). Compound (3) (4.4 g, 11.4 mmol) was dissolved in 110 mL of THF and cooled to 0 °C. A 1 M solution of tetra-n-butylammonium fluoride (TBAF) in THF (11.4 mL, 11.4 mmol) was added dropwise to the solution of (3). The reaction mixture was stirred overnight at room temperature. The following day, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with water and then brine. The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. 3.9 g of crude 5-(furan-2-ylhydroxymethyl)imidazole-1-sulfonic acid dimethylamide (4) was obtained. Compound (4) (1.0 g, 3.7 mmol) was dissolved in 37 ml of dichloromethane, and 1.6 g (18.5 mmol) of manganese dioxide was added to the solution. The reaction mixture was stirred overnight at room temperature and then filtered through Celite. The solvent was removed from the eluent under reduced pressure.

Flash chromatography using a 1:1 mixture of ethyl acetate and hexane afforded 0.69 g (2.6 mmol) of 5-(furan-2-ylcarbonyl)imidazole-1-sulfonic acid dimethylamide (5). Compound (5) (0.69 g, 2.6 mmol) was dissolved in 26 mL of THF.

The solution was cooled to -78°C. 1.7 ml (5.1 mmol) of a 3 M methylmagnesium chloride solution was added. After stirring at -78°C for 1.5 hours, the reaction mixture was warmed to room temperature and stirred for another hour. The reaction mixture was quenched with water and then extracted with ethyl acetate.

The organic layer was washed with water and then brine. The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. Crystallization from ether/hexane gave 0.39 g (1.4 mmol) of 5-(1-furan-2-yl-1-hydroxyethyl)imidazole-1-sulfonic acid dimethylamide (6). An additional 0.19 g of compound (6) was obtained. Compound • 9 ·· ·· ·· ·· ·· ·· · · 4 ·· ·· ·· ·· ·· ·· ·· ·· ·· ·· ·· ·· ·· ·· ·· ·· ·· ········································································································································································································

The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. Flash chromatography using ethyl acetate:hexane 2:1 gave 0.53 g (2.0 mmol) of 5-(1-furan-2ylethyl)imidazole-1-sulfonic acid dimethylamide (7). Compound (7) (0.34 g, 1.3 mmol) was dissolved in 10 mL of 1.5 N HCl and heated under reflux for 30 min and then stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and then basified with 2 N NaOH. The organic layer was washed with water and then brine. The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. Flash chromatography (10:1 chloroform/methanol) afforded 0.1 g (0.62 mmol) of 4(5)-(1-furan-2-ylethyl)-1H-imidazole (8) (L).

¹ H NMR (300 MHz, CDCl ₃ ) 7.56 (m, 1H), 7.33-7.34 (m, 1H), 6.81 (m, 1H), 6.29-6.31 (m,

1H), 6.06-6.07 (m, 1H), 4.22 (q, J=7.2 Hz, 1H), 1.63 (d, J=7.2 Hz, 3H).

Example M

Preparation procedure for 4(5)-(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)-4-methyl-1H-imidazole:

_{SO2NMe2 ​}

1) n-BuLi

2) TBDMSCI

θ ^Η SO ₂ NMe ₂

θ ^Η SO ₂ NMe ₂ N >-TBS

TBAF

Et,SiH

CF,CO ₂ H

_{CH2C12 ​}

1.5 N HCl reflux

Procedure

4-Methyl-1-(dimethylsulfamoyl)imidazole (1) (2.0 g, 10.6 mmol) was dissolved in 42 mL of anhydrous THF and cooled to -78 ^° C. n-BuLi (6.6 mL, 10.6 mmol) was added dropwise to solution (1). The resulting solution was stirred for 30 min at -78°C. Tert-butyldimethylsilyl chloride (TBSCI) (1.6 g, 10.6 mmol) in 10 mL of THF was added to the reaction. The reaction mixture was warmed to room temperature and stirred overnight. The next day, the reaction mixture was cooled to -20°C and 7.3 mL (11.6 mmol) of n-BuLi was added. After stirring for 30 min at -20 °C, 1,4-benzodioxane-6-carboxaldehyde (2) (1.92 g, 11.7 mmol) in 10 mL THF was added to the reaction mixture. The reaction mixture was warmed to room temperature and stirred for 3 h. The reaction mixture was quenched with water and diluted with ethyl acetate. The organic layer was washed with water and then with brine. The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. Flash chromatography (1:2 ethyl acetate/hexane) gave 3.9 g (8.4 mmol) of 2-(t-butyldimethylsilyl)-5-[(2,3-dihydrobenzo[1,4]dioxin-6-yl)hydroxymethyl]-4-methylimidazole-1-sulfonic acid dimethylamide (3). Compound (3) (1.0 g, 2.14 mmol) was dissolved in 21 mL THF. A 1 M solution of tetra-n-butylammonium fluoride (TBAF) in THF (2.35 mL, 2.35 mmol) was added dropwise to solution (3). The reaction mixture was stirred for 30 min at room temperature. The reaction mixture was quenched with water and then extracted with ethyl acetate. The organic layer was washed with water and then with brine. The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. Flash chromatography using ethyl acetate as eluent gave 0.75 g (2.12 mmol) of 5-[(2,3-dihydrobenzo[1,4]dioxin-6yl)hydroxymethyl]-4-methylimidazole-1-sulfonic acid dimethylamide (4). Compound (4) (0.75 g, 2.12 mmol) was dissolved in 28 mL of dichloromethane, and 2.7 mL (17.0 mmol) of triethylsilane and 5.2 mL (67.8 mmol) of trifluoroacetic acid were added. The reaction was stirred overnight at room temperature and then quenched with water and neutralized with solid sodium bicarbonate. The organic layer was washed with water and then brine. The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. Flash chromatography using ethyl acetate:hexane (3:1) gave 0.63 g (1.87 mmol) of 5-(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)-4methylimidazole-1-sulfonic acid dimethylamide (5). Compound (5) (0.63 g, 1.87 mmol) was dissolved in 10 mL of 1.5 N HCl and heated under reflux. The reaction mixture was diluted with ethyl acetate and neutralized with solid sodium bicarbonate. The organic layer was washed with water and then with brine. The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. Crystallization from ether/hexane gave 0.33 g (1.43 mmol) of 4(5)-(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)-4-methyl-1H-imidazole (6) (M).

¹ H NMR (300 MHz, acetone-d ⁶ ) 7.37 (s, 1H), 6.66-6.67 (m, 3H), 4.18 (s, 4H), 3.73 (s, 1H),

2.13 (s, 3H).

Example N

Preparation procedure of 2-(3H-imidazol-4(5)-ylmethyl)-3,4,5,6,7,8-hexahydro-2H-naphthalene 1-one (N-1), 4(5)-(2,3,4,4a,5,6,7,8-octahydronaphthalen-2-ylmethyl)-1H-imidazole (N-2) and 4(5)-(1,2,3,4,5,6,7,8-octahydronaphthalen-2-ylmethyl)-1H-imidazole (N-3):

O

1)NaOH/EtOH reflux

2) 40% _{H2SO4 reflux}

N

H

H ₂ NNH ₂ ,

NaOH, reflux diethylene glycol

Procedure

1-Decalone (10.0 g, 66 mmol) and 4(5)-imidazolecarboxaldehyde (6.3 g, 66 mmol) were added to 100 mL of ethanol. To the solution was added NaOH (5.2 g, 130 mmol) in 20 mL of water. The reaction mixture was heated under reflux for 5 days. The reaction mixture was cooled to room temperature and basified with aqueous HCl. The solution was extracted with THF/ethyl acetate. The organic layers were combined and washed with brine. The organic phase was dried over magnesium sulfate and the solvent was removed under reduced pressure to give the crude product. The crude product was refluxed in 40% H2SO4 for 1 day. The reaction mixture was cooled to room temperature and basified with saturated K2CO3 solution. The solution was extracted with THF/ethyl acetate. The organic layers were combined and washed with brine. The organic phase was dried over magnesium sulfate and the solvent was removed under reduced pressure. Purification by flash chromatography (15:1 _CH3Cl /1\/leOH) gave compound N-1 (4.9 g, 32% yield).

¹ H NMR: 7.55 (s, 1H), 6.77 (s, 1H), 3.08-3.14 (m, 2H), 1.52-2.46 (m, 13H).

The free base hydrochloride of compound N-1 (3.0 g, 11 mmol) was prepared with NaOH and then added to diethylene glycol (100 mL). Hydrazine hydrate (3.2 mL, 100 mmol) was added to the solution and the reaction mixture was allowed to stir overnight at room temperature. NaOH (3.1 g, 77 mmol) was added and the solution was heated to reflux for 5 days. The reaction mixture was cooled to room temperature and diluted with water. The solution was extracted with THF/ethyl acetate. The organic layers were combined and washed with brine. The organic phase was dried over magnesium sulfate and the solvent was removed under reduced pressure. Purification by flash chromatography (8:1 CH3Cl/MeOH) afforded N-2 (0.64 g, 27% yield).

¹ H NMR: 7.58 (s, 1H), 6.76 (s, 1H), 5.24 (d, J=4.3 Hz, 1H), 0.91-2.58 (m, 16H).

Compound N-2 (1.0 g, 4.6 mmol) was added to 10 mL of concentrated HCl. The solution was stirred at room temperature for 30 min and then neutralized with K2CO3. The solution was extracted with THF/ethyl acetate. The organic layers were combined and washed with brine. The organic phase was dried over magnesium sulfate and the solvent was removed with ⁵³

I • · • 4 · · '·' 4 4 · ·, · ·

4 4 4··· · 4 · β

4444··· ·· 4 4 · · 4 4

4 4 4 4 4 4 · · ·

4 4 4 4 44 44 44 reduced pressure. Purification by flash chromatography (15:1 CHCl/MeOH) gives compound N-3.

¹ H NMR: 7.54 ($, 1H), 6.74 (s, 1H), 2.45-2.52 (m, 3H), 1.46-1.97 (m, 14H).

Example O

Preparation procedure for 4(5)-octahydropentalen-2-ylmethyl)-1H-imidazole hydrochloride:

pcc,ch ₂ ci ₂ rcflux

H '0

Procedure

A. According to the synthesis procedure of White and Whitesell, Synthesis, pp. 602-3 (1975), ether (10 ml) was placed in a flask dried over a flame and cooled to 0°C and kept under argon. Then n-butyl lithium (35 ml of a 2.5 M solution in hexane, 2.2 equivalents) was added, followed by the slow addition of diisopropylamine (14 ml, 2.5 equivalents) and the mixture was allowed to stir at 0°C for 30 minutes. To the lithium diisopropylamide solution thus prepared was added cyclooctene oxide (5.0 g, 1.0 equivalent). The mixture was stirred at room temperature for 1 day and then refluxed under argon for 2 days. The reaction was quenched by addition of NH4Cl. The solution was extracted with THF/EtOAc. The organic extracts were combined, washed with brine, dried over magnesium sulfate, and concentrated in vacuo to give 1-hydroxy-octahydropentalene as a tan oil. The compound was used in the next step without further purification.

B. The alcohol thus obtained (5.0 g, 1 equivalent) was dissolved in dichloromethane (200 mL) and pyridinium chlorochromate (13 g, 1.5 equivalent) was added to the solution and the mixture was stirred at room temperature for 1 day. The solution was then filtered through a short column of SiO ₂ using diethyl ether as eluent. The resulting solution was concentrated in vacuo to give a pale greenish-yellow oil which was used without further purification in the next step.

C. Octahydro-pentalen-1-one (5.0 g, 1.0 equiv) from the previous step was added to 4(5)-imidazolecarboxaldehyde (3.8 g, 1.0 equiv) and 40% H2SO4 (20 mL) and the mixture was maintained at 90 °C for 3 days. The reaction was then quenched by addition of ammonium hydroxide and extracted with tetrahydrofuran/ethyl acetate. The organic extracts were combined, washed with brine and dried over magnesium sulfate. The resulting aqueous layer was neutralized with HCl/NH4Cl. The aqueous layer was re-extracted as above and the combined organic fractions were concentrated in vacuo to give an orange solid.

D. This orange solid was dissolved in ethanol to which palladium on carbon (0.5 g) was added. The reaction flask was placed under a 0.74 Pa (40 psi) hydrogen atmosphere for 1 day. The reaction solution was filtered through Celite with additional ethanol used as eluent. The solution was concentrated in vacuo to give a tan oil. Purification by column chromatography using 17:1 chloroform/methanol gave the ketone product in an incompletely pure state.

Υ·' · · · · ·· ·· ·· ·-· · » · · *' ♦; · ·; ·······*«·· • ··*· · · · · · · .· · · · • « · · · · ···· ··· · ·· ·· ·· ··

E. The ketone function was then removed by adding the product from the previous step (8.2 g, 1.0 equiv.) to diethylene glycol (80 mL) and hydrazine hydrate (13.0 g, 1.0 equiv.). This mixture was stirred overnight and then potassium hydroxide (11.0 g, 5.0 equiv.) was added and the solution was refluxed for 1 day. The reaction solution was cooled to room temperature and washed with water. The solution was extracted with THF/EtOAc and the combined fractions were washed with brine, dried over magnesium sulfate and concentrated in vacuo to give a yellow oil. The monohydrochloride salt was prepared by dissolving this oil in anhydrous ethanol saturated with HCl and heating.

Example P

Procedure for the preparation of 7-(3H-imidazol-4(5)-ylmethyl)-6,7-dihydro-5H-isoquinolin-8-one (P1) and 7-(3H-imidazol-4(5)-ylmethyl)-5,6 ₎ 7,8-tetrahydroisoquinoline (P-2):

1) _H2 , Pd/C

2) K^· _f

P-l

P-2

Procedure

A. 3,4-lutidine (21.4 g, 1 equivalent) is dissolved in 200 ml of water at 20 °C and potassium permanganate is added in 6.32 g doses twice a day for 5 days (total amount 63.2 g, 2 equivalents). After 5 days, the solution is placed in a freezer, then allowed to thaw and • 9' · » 4 4' 9' » 4' · «.! ·' ♦.

• · » 4 · · · · · · · « ·····« 9* 9 « · ® 9 9

9 9 9 9 4 9 4 4 «

4 4' 4 »4 4 4 <41 4 4 filtered through Celite. The resulting colorless solution was concentrated at 90 °C on a rotary evaporator to give a white solid. This solid was recrystallized from 5N HCl to give 9.56 g of white crystals. NMR showed a mixture of two regioisomers, with the desired isomer being the majority product.

B. These crystals were heated at reflux in anhydrous ethanol saturated with HCl gas under an argon atmosphere for 6 hours. The ethanol was then removed from the solution using a rotary evaporator and the residue was dissolved in 100 mL of water and the pH was adjusted to between 7 and 8 with solid sodium bicarbonate. The aqueous phase was extracted with diethyl ether (3x) and the combined organic fractions were washed with brine, dried over magnesium sulfate, then filtered and concentrated to give a colorless oil (3.56 g, 10.8% yield).

C. Diisopropylamine (2.84 g, 1.3 equiv) was added via cannula to n-BuLi (11.21 mL, 1.3 equiv) in 100 mL anhydrous THF under argon at -78 °C to prepare lithium diisopropylamide in situ. To this solution was added via cannula the product from previous step B (3.56 g, 1 equiv) in 20 mL tetrahydrofuran and the mixture was stirred at -78 °C for 20 min. At this point, methyl acrylate (4.85 mL,

2.5 equivalents) in 20 ml of tetrahydrofuran. The solution was stirred for a further 2 hours and then quenched by the addition of 40 ml of 10% potassium acetate. The solution was allowed to warm to 20 °C and then concentrated on a rotary evaporator. The aqueous residue was extracted three times with chloroform. The combined fractions were washed with brine and dried over magnesium sulphate, filtered and concentrated to a black solid which was stored under high vacuum. Chromatography on silica gel with hexane/ethyl acetate (7/3 6/4) gave 2.41 g (58.2%) of the desired product which was used in the next step without further purification.

D. The material from Step C (0.48 g, 1 equivalent) was dissolved in 1 mL of 6 M HCl and heated at 105 °C for 16 h, then the solution was concentrated by rotary evaporation at 80 °C to a solid.

• 9 9 9 9 9 9 9 9 4 ·' φ 4 4 4 4 44 4 · 4 ·

4444 44 44 4 4 *4 4

4 444 4 4444

444 * 9 9 44 ·· ··

The residue was dissolved in 2 mL of water and neutralized with solid sodium bicarbonate. The neutralized solution was extracted with chloroform (3x) and the combined fractions were washed with brine, dried over magnesium sulfate and concentrated to give a colorless oil (0.456 g, 93.4%).

E. The isoquinolone (1.91 g, 1 equivalent) obtained in the previous step D was heated with 4(5)-imidazolecarboxaldehyde (1.25 g, 1 equivalent) at 110 °C in 15 mL of 40% sulfuric acid for 30 h. The reaction mixture was stored under argon at 0 °C for several days. The solution was then diluted with 20 mL of water and basified to pH 8.9 with NH4OH. The solids were collected by filtration and dried under high vacuum. The product, a yellow solid (2.81 g, 96.1%), contained a mixture of both positional isomers at the exo double bond.

F. The product from the previous step E was dissolved in 150 mL of methanol and Pd/C (0.412 g, 0.15 wt. equivalent) was added to this solution. The methanol solution was then saturated with H ₂ by repeated evacuations and backfilling with hydrogen. The solution was then stirred for 20 h under 1 atmosphere of H ₂ until no starting unsaturated material remained detectable by TLC. The solution was then filtered through Celite and concentrated to an oil. Chromatography on silica gel using dichloromethane and methanol (9/1) gave the pure product (1.853 g, 65.04%) as a white foam. This was dissolved in methanol to which fumaric acid (0.4817 g, 1.5 eq.) was added and the mixture was heated to dissolve the solids. The solution was slowly cooled to give off-white crystals (0.826 g, 74%), which represented compound P-1. Compound P-2 was obtained by hydrazine reduction using the same procedure as described in step E in the previous section.

Example O.

í>

Example Q

Preparation procedure of (Z)-6-(3H-imidazol-4(5)-ylmethylene)-7,8-dihydro-6H-quinolin-5-one (Q-1), (E)-6-(3H-imidazol-4(5)-ylmethylene)-7,8-dihydro-6H-quinolin-5-one (Q-2), 6-(3Himidazol-4(5)-ylmethyl)-7,8-dihydro-6H-quinolin-5-one (Q-3), 6-(3H-imidazol-4(5)ylmethyl)-5,6,7,8-tetrahydroquinodihydrochloride (Q-4) and 6-(3H-imidazol-4(5)-ylmethyl)octahydroquinolin-5-one (Q-5):

NaN ₃ . CH ₃ CN, CU

N, » · · · ♦: · 9 .· · ·· ₊ · · » · • · · · '·>> · · ·

H,O. Na ₂ S ₂ O3 DMF, NaN ₃

CH2Cl2, Ph3P, rt

40% _H2SO4 , ₉₀ °C

N,

N=PPh ₃

1) hydrazine. diethylene glycol

2) KOH

3) Ha

Λ/fcroUín

Pď/C ΐα HoutuVlo tsowietru

Li/ _NH3

H ₂ . Pd/C MeOH tt tt. 'tt tttt, ·· tttt tttt • tttt · tt' · tt · • · tttt tttttt tt • · tt · *· 'tt · · · • tttt · · tttt « tttt tttt tttt ··

Procedure

A. The reactive azido reagent from the first step is prepared in situ by adding iodine monochloride (67.6 g, 1.15 equiv) in 50 mL acetonitrile dropwise via a dropper to a stirred slurry of sodium azide (58.84 g, 2.5 equiv) in 350 mL anhydrous acetonitrile at -10 °C under argon. The addition is complete within 30 min, the mixture is stirred for another 30 min, and cyclohexenone (34.81 g, 1.0 equiv) is added via syringe and then stirred for another 20 h at 20 °C. The mixture is then poured into 1 liter of water and extracted with three 200 mL portions of diethyl ether. The combined fractions are washed with 5% sodium thiosulfate and then brine. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo at 20 °C. The residue was dissolved in 1 L of DMSO at 0 °C and a second portion of NaN3 was added and the mixture was stirred while warming to ambient temperature. This mixture was then diluted with 2.5 L of ice water and extracted ten times with dichloromethane (10 x 250 mL). The combined fractions were concentrated by rotary evaporation to a volume of -1 L and this concentrate was extracted three times with 250 mL of water and then with brine, then dried over magnesium sulfate and concentrated to a dark oil (39.5 g) and stored at -40 °C. The oil was purified by chromatography on silica gel using a 9/1 to 8/2 hexane:ethyl acetate mixture. Two isomers are obtained, the first with an azido group alpha to the ketone function in an amount of 13.22 g with a 26.6% yield. The beta-isomer is obtained in an amount of 15.825 g with a 32.0% yield.

B. Triphenylphosphine is dissolved in 20 ml of dichloromethane and placed under an argon atmosphere at 20 °C. The beta-isomer obtained as described above is added via cannula to the stirred solution and maintained at 20 °C for 2 hours. As the reaction proceeds, nitrogen is evolved from the solution and after 2 hours no remaining starting material can be detected by TLC. The solution is concentrated and passed through a silica gel column with dichloromethane as the liquid phase, which is then exchanged with a mixture of • · · <

♦ » ·· ► * · · » « ·Φ dichloromethane:methanol 95/5 as eluent. The amidophosphonate intermediate is obtained in an amount of 2.139 g with a 65.1% yield.

C. The amidophosphonate is dissolved in 100 ml of anhydrous o-xylene and then 10% Pd/C is added with constant stirring. Freshly distilled acrolein is added to the mixture using a syringe and the mixture is heated under reflux for 4 hours. The remaining acrolein is then added and the heating under reflux (finger condenser) is continued for another 44 hours under argon. After this time, some remaining intermediates can be detected by TLC, so another 0.5 g of Pd/C is added and the mixture is heated under reflux again for another 8 hours. The mixture is cooled to room temperature, filtered and concentrated on a rotary evaporator to eliminate excess acrolein until about 100 ml of o-xylene solution remains. The solution is cooled by adding ice and extracted three times with 1N HCl. The combined aqueous fractions were extracted 3x with Et2O. The aqueous phase was then cooled to 0 °C and the pH was adjusted to about 10 with concentrated NaOH. The aqueous fraction was then extracted 5x with 100 ml portions of chloroform. The combined chloroform fractions were washed with water and then brine and dried over magnesium sulfate, filtered and finally concentrated to give 3.51 g (84.4% yield) of 7,8-dihydro-6H-quinolin-5-one as an oil.

D. Condensation of 4(5)-imidazolecarboxaldehyde with the quinolinone described in Step E of Example P affords both compounds Q-1 and Q-2.

E. The exo double bond is then reduced with palladium on charcoal as described in Step E of Example P above to give two products which, upon separation by chromatography, provide Q-3 and A.

F. The keto group is removed by the same hydrazine reduction as described above in

Step E of Example O to form Q-4.

Φ φ Φ φ *· ·* φφ • Φ φ φφφφ φφφφ

ΦΦΦ Φ φ φφ · φ φ · ♦ φφφφ Φ φ φ · φφφ Φ φ φ • · φφφφ φφφφ

G. Product Q-5 with a fully reduced quinoline ring is obtained by standard lithium/ammonium reduction of compound A. (Li, 10 equivalents in NH ₃ at -78 °C for 10 min, quenched with NH ₄ OH, gradual warming with evaporation of NH ₃ ).

Example R-1

Preparation procedure for (E)-6-(3H-imidazol-4(5)-ylmethylene)-7,8-dihydro-6H-quinoxalin-5-one:

Procedure:

A. A mixture of 5,6,7,8-tetrahydroquinoxaline (23.75 g, 1 equivalent), benzaldehyde (19.81 mL, 1.1 equivalent) and acetic anhydride (33.4 mL, 2.0 equivalent) was stirred for 15 hours at 150 °C under argon. After this time, TLC showed mostly the desired product with small amounts of starting materials. The starting materials were removed by vacuum distillation using a Vigreux column at 170 °C. The residue in the vessel was then subjected to Kugelrohr distillation at a temperature of 170 to 220 °C. The first fraction was slightly contaminated with starting materials (4.71 g). The second fraction was clean (18.93 g). Applying high vacuum to the first fraction causes its crystallization. The combined fractions yield 20.11 g of compound in 51% yield.

B. The product from the previous step A is dissolved in 100 ml of methanol and warmed slightly, then cooled to -35 to -40 °C and ozone is bubbled through the solution. After a few minutes, the starting material begins to crystallize from the solution. The solution is warmed and another 200 ml of methanol is added and the reaction is repeated. After 30 minutes, the solution becomes pale blue.

Nitrogen was bubbled into the solution for 30 minutes, then methyl sulfide (3.5 mL) was injected into the solution, then the solution was stirred for a further 30 minutes at -35 °C and allowed to warm to ambient temperature with constant stirring. After 48 hours at 20 °C, the mixture was steam distilled to remove the solvents and 8.4 g of a yellow-brown oil residue was obtained. The residue was dissolved in diethyl ether and extracted with 3 x 25 mL portions of 1 N HCl. The combined aqueous fractions were washed 3 x with diethyl ether. The aqueous solution was gradually basified with concentrated NaOH to pH 8. The free amine was then extracted from the aqueous phase with chloroform (3x). The combined chloroform extracts were washed twice with brine, dried over MgSO4 and concentrated to a yellow oil (3.01 g). After 1 hour of storage under high vacuum, 2.97 g remained. This amount was recrystallized from diethyl ether to give 2.35 g of a bright yellow solid. Yield 67.5%.

C. 7,8-Dihydroquinoxalin-5-one and 4(5)-imidazolecarboxaldehyde (Aldrich Chemicals) were resuspended in 75 mL of anhydrous tetrahydrofuran at 20°C under argon followed by the addition of piperidine and then acetic acid. The mixture was stirred for 16 hours at 20°C.

After 20 hours, no trace of quinoxalone remains detectable by TLC. The solids are collected by filtration and washed with a small amount of tetrahydrofuran followed by chloroform. The solid is dried under high vacuum to give 6.58 g of compound R-1. Yield 90.3%.

»•4 • 4

44 • 4 4 4

4 4» • 4 4 4 • 4 4 ·

49 ·«

4 4 4

4 4 4

4 · 4

4 4 V

44

Example R-2 and R-3

In a similar manner to compound R-1, 5,6,7,8-tetrahydroisoquinoline (5.42 g, 1 equivalent, Aldrich) was mixed with benzaldehyde (5.182 g, 1.2 equivalent) and acetic anhydride (6.309 g, 2.0 g), which was vacuum distilled and used without further purification in the subsequent step. Yield (impure): 8.28 g.

The crude product (7.96 g) from the previous step was subjected to ozonolysis as described in Step B above. A final chromatography step yielded 5.18 g of a pale oil. Yield 97.8% assuming pure starting materials. The resulting 7,8-dihydro-6Hisoquinolin-5-one (1.692 g, 1 equivalent) was condensed with 4(5)-imidazolecarboxaldehyde as described above in Step C to give 2.23 g of an unsaturated compound analogous to compound R-1 of the previous scheme in 92.8% yield. This product was treated with palladium on carbon as described in Step F of Example P, reducing the exo double bond to give 6-(3H-imidazol-4(5)-ylmethyl)-7,8-dihydro-6H-isoquinolin-5-one (R2) in 52% yield.

The above ketone was reduced with hydrazine and converted to the fumarate salt according to the procedure in Example P Step F. Reduction yield: 62%. Fumarate salt yield after recrystallization: 30.4% 6-(3H-imidazol-4(5)-ylmethyl)-5,6,7,8-tetrahydroisoquinoline (R-3).

Example S

The method for measuring alpha-agonist selectivity involves the determination of RSAT (Receptor

Selection and Amplification Technology (receptor selection and amplification technique), as described in Messier et al. (1995) High throughput assays of cloned adrenergic, muscarinic, neurokinin and neurotrophin receptors in living mammalian cells,” Pharmacol.Toxicol. 76:308-11, which was adapted for use with alpha2-receptors. The assay measures the receptor-mediated loss of contact inhibition, which results in selective proliferation of cells containing the receptor in a mixed population of confluent cells. The increase in cell number is determined by transfecting a suitable marker gene, such as beta-galactosidase, whose activity can be readily measured in a 96-well plate. G protein-activating receptors, such as G _q , enhance the response. Alpha2 receptors, which normally bind to G j , activate the RSAT response when co-expressed with a hybrid G _q protein that has a recognition domain Gj receptor, denoted G _q /j ₅ ² . See Conklin et al. (1993) Substitution of three amino acids switches receptor specificity _of G _q a to that of Gja.” Nature 363:274-6.

NIH-3T3 cells are plated at a density of 2 x 10 ⁶ cells per 15 cm dish and maintained in Dulbecco's modified Eagle's medium supplemented with 10% fetal calf serum. After one day, the cells are co-transfected by calcium phosphate precipitation with mammalian expression plasmids encoding p-SV-beta-galactosidase (5 to 10 mg), receptor (1 to 2 mg), and G protein (1 to 2 mg). 40 mg of salmon sperm DNA may also be present in the transfection mixture. Fresh medium is added the following day, and 1 to 2 days later, the cells are harvested and frozen in 50 aliquots for assay. The cells are thawed and 100 ml is added to 100 ml aliquots containing various drug concentrations in 96-well dishes (all done in triplicate). Incubation is continued at 37 degrees Celsius for 72 to 96 hours. After washing with phosphate-buffered saline, beta-galactosidase activity is determined by adding 200 ml of chromogenic substrate (comprising 3.5 mM o-nitrophenyl-beta-D _- galacto67 • · · ···· · The potency or intrinsic activity is calculated as the ratio of the maximum effect of the drug to the maximum effect of the standard full agonist for each receptor subtype. Brimonidine, also called UK14 304-18, is used as the standard agonist for the alpha^ and alpha _2C receptors. Oxymetazoline is the standard agonist used for the alpha _2B receptor.

Table 1 below lists the intrinsic activity values for alpha2-adrenoceptor subtypes as determined by RSAT assays for the compounds of Examples B through R above and for some adrenergic compounds that do not have selective agonist activity at the alpha2B or alpha2B/alpha2C subtype(s). At the alpha2A subtype, the compounds of these Examples are inactive or exhibit low potency (less than or equal to 0.4). They have higher potency at the alpha2B and alpha2C subtypes than at the alpha2A subtype. Therefore, unlike ophthalmic alpha2 adrenoceptor compounds such as clonidine and brimonidine, the compounds of Examples B through R can selectively activate alpha2 adrenoceptor subtypes other than the alpha2A subtype.

• · • · b»)

Table 1: Intrinsic activity related to brimonidine/oxymetazoline

Example Structure/Compound Brimonidine Alpha2A Oxvmelazolin Alfa2B Brimonidine. Alfa2C oxymetazoline 0.63 i,.O 0 _f 58 clonidine 0.78 0 _f 75 0.55 brimonidini ¥ 0.93 ¥ 4(5)-(3-methyl-thiophene-2- ylmethyl)-1H- imidazole 0.43 ¥ 0.5 D-3 v> HN-V bicyclo[2.2.1]hept-2-yl oxazolidin'2-ylidene amine 0 °i ⁴ 0

phil· • 4 ··

Example Structure/Compound Brimonidine. Oxymetazoline>. Brimonidine 1 Alpha2A Alpha2B A!fa2C

P-l HN^/ oxazolidin-2-ylidene. -(3-phenyl bicyclo[2.2.1]hept-2-yl)amine 0 0.47 0 F ςχ,/ϊΧ 6-(Imidazolidin-2-ylideneamino)-5-methyl-4H-benzophenyl,4}oxazin-3-one. 0.9 0.2 G HCI r-nh Ν^Ν'γ^ΝΗ ^H o imidazolidin-2-ylidene-(5methyl-3,4-dihydro-2Hbenzo[1,4]oxazin-8-yl)amine:;, UCI ffSl θ/ ¹ 0.87 0.33 JJ. ~CA0 4(5)-cyclohexylmethyl-1H- θ,ι 0.83 0

• · • · · · · · · · « • · ···· · · · «

Example Structure/Compound Brimonidim Alpha2A OxYmelazolim Alpha2B Brimonidiru A/fa2C imidazole· E-1 στ.00 Η 1 Imidazolidin-2-ylidene-(4-methyl-3,4-dihydro-2H-benzo(1,4]oxazin-6-yl)amine 0.33 _About 83 0(35 M < ^z I TjO - A 4(5)-(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)4-methyl-1H-imidazole tp 0 ₍ 97 0(27 C-2 /= ^N V FA 4(5)-thiophen-2-ylmethyl-1H-imidazole 0.23 In °1 ⁵ C-l /= ^N \ f=\ 4(5)-thiophen-3-ylmethyl-1H imidazole 0 _About 83 0

Example Structure/Compound Brimonidine· Alpha2A Oxymetazoline Alfa2B Brimonidine Alfa2C C-9 /= ^N > /po 4(5)-benzo[b]thiophen-2ylmethyl 1-1H-imidazole OjO6 0.88 0.43 C-3 4(5)-(5-Methylthiophen-2ylmethyl)-1H-imidazole ° ₍₁ 0.88 0.43 C-8 /=t ΓΊ 4(5)-Benzyl-1H-imidazole ° _f 3 0.9 0.4 H /= Π 4(5)-Phenylsulfanes 1-1Himidazole 0.2 0.93 0 15 C-5 /= ^N . o 4(5)-furan-2-ylmethyl-1H-imidazole 0 • In 0.4

iΎ ó it ···· · *

Example Structure/Compound Bnmonidine Alpha2A Oxymetazoline· Alfa2B Brimonidine Alfa2C B-3b 0 in 0 4(5)-(1,2,3,4-tetrahydronaphthalen-2'ylmethyl)-1H-imidazoyl L2 0 0.8 0 (S)-4(5)-(1,2,3,4tetrahydronaphthalen-2ylmethyl)-1H-imidazole· - L3 /= ^N ' θ,· ¹ 1 0.15 1 (R)-4(5)-(1,2,3,4tetrahydronaphthalen-2ylmethyl)-1H-imidazole L /= ^N > r\ 0.23 0.9 0.57 4(5)-(1-Furan-2-ylethyl)-1-Himidazole. C-6 0.2 0.67 In 4(5)-Furan-3-ylmethyl-1-Himidazole

b

7' '· · · * • V 9 Φ « * · · • · · ·

Example Structure/Compound Brimonidine . AIfa2A , Oxymetazoline Alfa2B Brimonidine Alfa2C C-4 4(5)-(5-Chlorothiophen-2-ylmethyl)-1H-imidazole 0.05 0)82 °l ⁵ D-2 HN-V oxazoiidin-2-yiiden-(3-o-tolyl bicyclo(2.2.1]hept-2-yl) amine 0.25 0.75 0 C-10 /=t ΐτζ~) 4(5)-Benzofuran-2-ylmethyl 1H-imidazole 0.05 0.48 °/> C-7 -ΟΰΛ 4(5)-(5-Methylfuran-2ylmethyl)-1H-imidazole 0 _} 08 0.73 Oh, ²

Example Structure/Compound Brimonidine- Alpha2A Oxymeazoline; Alfa2B Brimonidine Alfa2C B-3a /= ^N X fYY θί ¹ 0.8 i 0.07 i about 2-(3H-imidazole-4(5)- ylmethyl)-3,4-dihydro-2H- naphthalene-l-oru and _{CH3SO3H ​} 0 In T 4(5)-(1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-4,5-dihydro-1Himidazo- ^1methane <5>it|foha'| B-2a /= ^N X ( Yη 0 0^63 0 _? 15 about 3-(3H-imidazol-4(5)ylmethylene:)chroman-4-one' B-2b A /x /= ^N x ( 0 0(77 0 About 3-(3H-imidazole-4(5)- ylmethyl)chroman-4-one' 1

• · · · · · · · · · • ·· ·· ·· ··

Example Structure/Compound Brimonidine Alpha2A Oxymetazoline . Alpha2B Brimonidine Alfa2C B-2d _N 0 0 _f 6 0 4(5)-chroman-3-ylmethyl-1H- imidazole B-2c /= ^N V ( Y^i OH 0 0 _f 65 0 3-(3H-imidazol-4(5)ylmethyl)chroman-4-ol -- B-9a H 0 _{ 08 0.46 0 4(5)-(4,5,6,7- tetrahydrobenzo[b]thiophen-5ylmethyl)-1H-imidazole B-4a /= ^r ; (TI 0 0^75 θί ¹ 4(5)-(4-methyl-1-1,2,3,4-tetrahydronaphthalen-2ylmethyl)-1H-imidazole 1

Example Structure/networking Brimonidim Alpha2A Oxymeiazobn Alpha2B Brimonidine Alfa2C B-4b /= ^N , fjPj op 0/7 0.6 about 2-(3H-imidazole-4(5)- yimethyl)~4-methyl-3,4- dihydro-2H-naphthalene-1-or. B-lIb 0 0.3 0 6-(1H-imidazol-4(5)ylmethylene.:)-6,7,8,9-tetrahydrobenzocyclohepten-5-one : B-6 HCl N 0 0 _? 35 0 4(5)-thiochrom-3-ylmethyl 1H-imidazole HCl B-5b /= ^N \ ( 0 0 _ø 5 0.2 l About 3-(3H-imidazoI-4(5)- ylmethyl)thiochroman-4-one

i»Á

Example Structure/Compound Brimonjoin. Alpha2A Oxymelazolir ' Alfa2B Brimonidine'. Alfa2C B-5a /= ^N V ( Υη 0 0.5 0.^37 about 3-(3H-imidazol-4(5)ylmethylene.nhiochroman-4- he B-7a /= ⁿ in yO 0 In 0 about 2-(3H-imidazol-4(5)ylmethylene)}ndan-1-one B-Ila OCTQ 0.4 In 0 4(5)-(6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ylmethyl)- 1 H-imidazole B-7b . r{) 0 0/3. about about 2-(3H-imidazol-4(5)ylmethyl)indan-1-one

4 4 • 4 44 44 44 ·· 4 4' 4' • 4 4' • 4 4 4 4 4 4 4 • 4 '4 4 4 4 4 4 4 4 4' 4 4 4 4 4 4 44 · 4 4'4 '4 4 4 4 4«

Example Structure/Compound Brimonioin Alpha2A Oxymeazoline. ’ Alfa2B Brimonidine' Alfa2C B-l HCI 0.15 0.45 0.3 4(5)-(7-Methoxy-1,2,3,4[tetrahydronaphthalene-2-ylmethyl)-! H-imidazole· , B-la 0.15 0.6 0 About 2-(3H-imidazole-4(5)- ylmethyl)-7-methoxy-3,4- dihydro-2H-naphthalen-1-one B-9b HCI /=*{ ΓΊό 0 0.68 0 _? 15 About 5-(3H-imidazol-4(5)ylmethyl)-6,7-dihydro-5H-benzo[b]thiophen-4-one', Account Cfi B-7c 0 0.9 0 4(5)-Indan-2-ylmethyl-1-Himidazole

·'* t* » ttttt · * · ttttt

Example Structure/Compound Brimonidine | Alpha2A Oxymetazoline Alfa2B Brimonidi»» Alfa2C B-JO /=N lij 4(5)-(4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2ylmethyl)-1H-imidazole * 0 ¥ 0 B-8b HCl - 4(5)-(7-methyl-1,2,3,4-tetrahydronaphthalen-2ylmethyl)-! H-imidazole· . KCI 0 0.6 0.2 B-8a /= ^N \ΠΠ O 2-(3H-imidazol-4(5)ylmethyl)-7-methyl 1-3,4-dihydro-2H-naphthalen-1-one 0 0.4 0 K-l /= ⁿ v nT) 4(5)-(4,5,6,7-tetrahydrobenzo[b]thiophen-2ylmethyl)-1H-imidazole 0 0.53 0

4.1 ·· 44 4« 44 • · · < 4 4 4

444 44««

Example Structure/Compound Brimonidine. Alpha2A Oxymetazoline Alfa2B Brimonidine. Alfa2C C-12 ^B 'n-L G-N-H 0.2 1.3 oh, ³ 4(5)-(4-Bromothiophen-2ylmethyl)-1H-imidazole C-13 ^Ph M—\ r-NH OM? 0 0.5 0 4(5)-(4-phenylthiophen-2-ylmethyl)-1H-imidazole K-3 /= ^N , irCf> 4(5)-(5,6-dihydro-4Hthieno[2,3-b]thiopyran-2yimethyl)-1H-imidazole· 0 0.37 0 K-2 1—1 /r-NH n 0 oh, ⁷ 0 4(5)-(5-tert-Butylfuran-2-ylmethyl)-1H-imidazole C-l 1 --- _r NH AU' 0.2 °i ⁵ 0 4(5)-(5-Ethylfuran-2-ylmethyl)-1H-imidazole

• φ

Brimonidine . Alpha2A

Alfa2B ·· »» ► φ φ « » · φφ

Example

Structure/compound

Oxymetazoline

Brimonidine

Alfa2C

C-14 í5 HCI 0.27 °r ⁷ In 4(5)-(4-methylthiophen-2ylmethyl)-1H-imidazole, N-I Oh Ha 0.24 0.75 0.26 2-(3H-imidazole-4(5)- ylmethyl)-3,4,5,6,7,8- hexahydro-2H-naphthalene-1- or ,, Hq 0=3 About θ) ¹ 0.9 i 0.23 1 6-(3H-imidazole-4(5)- ylmethyl)-7,8-dihydro-6H- quinolin-5-one 0=2 0.1 0.87 0.13

4 · • 4 ·· ·· · • 4 4 4 • 4 • • • 4 4 • • 4· 4 • • 4 • 4 • 4 4 4 · • • 4 • »*· 4 4 4 • · * » • 4

Example Structure/Compound Brimonidine Alpha2A Oxymetazoline·· . Alfa2B Brimonidine· Alfa2C (E)-6-(3H-imidazol-4(5)ylmethylene· -7,8-dihydro-6H- quinolin-5-one From w H (Z)-6-(3H-imidazol-4(5)ylmethylene'-7,8-dihydro-6H-quinolin-5-one. 0 0.75 0.2 N-2 _H 0UOO 0 °r ⁵ 005 4(5)-(2,3,4,4a,5,6,7,8octahydronaphthalen-2ylmethyl)-1H-imidazole QdL 2HC1 _n 0.8 ^about .> 6-(3H-imidazol-4(5)ylmethyl)-5,6,7,8-tetrahydroquinoline, dihydrochloride·

A Φ » ΦΦ «V ·* Φ·

Φ.

Example Structure/Compound Brimonidine Alpha2A Oxymelazoline Alpha2B Brimonidine . Alfa2C 0 ^you are 0 0(67 0(1 4(5)-octahydro pentalen-2ylmethyl-1H-imidazole. hydrochloride B-9c H HCl 0 0.3 0 5-(octahydro benzo[b]thiophen-5-ylmethyl)1H-imidazole . hydrochloride R-3 (HO ₂ C-CH),. ₅ 0 0 _f 6 ¥ 6-(3H-imidazol-4(5)ylmethyl)-5,6,7,8-tetrahydroisotphinoliyl· , fumarates R-2 2 HCI about 0 0.6 0.4 6-(3H-imidazol-4(5)ylmethyl)-7,8-dihydro-6-Hisoquinolin-5-ome, dihydrochloride.

<>'' · 4 ·· ·· Φ· ·· · ··?*_··»· • · · ···· ····

Example Structure/Compound Brimonidine Alpha2A • «ati Oxyme^pline * Alpha2B > · · · » »-, Brnnonidine Alpha2C R-1 ýjjQĎ o °z ³ 0.8 0.4 (E)-6-(3H-imidazol-4(5)ylmethylerc)-7,8-dihydro-6H-inoxalin-5-one! Ed _H 0--QCn / _J=qAo W / 0 0.4 0 7-(3H-imidazol-4(5)ylmethyl)-6,7-dihydro-5-Hisodiolin-8-one, fumarate? P-2 C 0 _0; 4 0 7-(3H-imidazol-4(5)ylmethyl)-5,6,7,8-tetrahydro- isocM nolur, fumarate N-3 H0UOO 0 0.75 0 /HQzCU, J \ CQ^ 4(5)-(1,2,3,4,5,6,7,8octahydronaphthalen-2ylmethyl)-1H-imidazole, fumarate - From about 0 1.0 0 • 6-(3H-imidazol-4(5)-ylmethyl)-octahydroquinolin-5one

Example T

Intraocular pressure (IOP)-lowering and sedative side effects.

Intraocular pressure (IOP) measurements were performed in fully conscious female Cynomolgus monkeys weighing 3 to 4 kg, with a persistently elevated IOP induced in the right eye by photocoagulation of the trabecular meshwork using an argon laser. The animals were available for use for approximately 2 months after surgery. During the experiments, the monkeys rested in specially constructed chairs (Primate Products, San Francisco) and were fed orange juice and fruit ad libitum. IOP was measured using a Digilab pneumatonometer model 30R (Alcon, Texas).

ml of anesthetic (proparacaine) was administered topically to each monkey before IOP measurement to minimize discomfort induced by tonometry. Two control measurements were performed before drug instillation and then periodic measurements were performed for 6 hours after drug application. Test compounds were administered to one eye only as a single 50 microliter drop; the other eye was instilled with the same volume of saline.

A number of alpha2B or alpha2B/2C selective compounds listed in the Examples were tested in monkeys. Surprisingly, as also shown in Table 2, all of these structurally distinct compounds lowered IOP in the test eye.

At the same time, the calming effect (sedation) was measured and evaluated according to the following scale: 0 = alert state, typical sound signals, movements, etc.; 1 = calm, less movements; 2 = slight sedation, occasional sound signals, animal responds to stimulation; 3 = sedation, no sound signals, occasional response to stimulation; 4 = animal is sleeping.

The compounds of the present invention also did not induce sedation. This contrasts with the effects of clonidine and brimonidine, which did induce sedation.

• · · · · · · · · · ·

Table 2. Effects of alpha ₂ -adrenoceptor agonists on IOP and sedation in conscious Cynomolgus monkeys observed after application to the eye in which intraocular pressure was unilaterally increased by argon laser photocoagulation. Measurements were made periodically for 6 hours. Sedation was rated subjectively during IOP experiments according to the following scale: 0 = alert state, typical sound signals, movements, etc.; 1 = calm, less movements; 2 = slight sedation, occasional sound signals, animal responds to stimulation; 3 = sedation, no sound signals, occasional response to stimulation; 4 = animal is asleep. The number of animals in the group was 6 to 9.

• · • · ·· ·· ·· ··

Table- 2 Maximum power from pre-treatment levels\%) Compounds Dose (%) Hypertensive eye Attenuation (0-4) 7±2 0-1 Clonidine; 0.1 i 25 ±4 1 0.3 41 ±5 2 Brimonidine·' θ, ¹ 25 ±3 1 0.3 40 ±4 2 J-l 1 26 ± 5 0 3 33 ±3 0 E-1 °l ³ 25 ±4 0 1 27 ±3 0 C-1 1 25 ±4 0 3 29±4 0 D-1 1 25.6 ± 3.9 f i 0 M 1 22 _f 5 ± 5 4 0 C-2 1 29.6 ± 5.5 1 f 0

• ·

C-9 In 1 13 _ø 7±4 _f 5 25.1 ±4.9 0 0 C-3 0.3 20.6 ±4.8 0 1 25.0 ± 6.4 0 C-8 1 31 2 ± 3 _f 3 0 B-3b <V 25.9 ± 3.5 0 in 31.2 ±4.3 0 C-4 °f ³ 17.7 ± 4.0 0 1 29.3 ± 4.9 0 C-7 1 32.3 ±5.7 0 J-2 0.03 12.4 ± 3.7 0 In 27.3 ±3.1 0 J-3 o.03 16.4 ±4.7 0 26.5 ± 3.8 1 i 0 B-2d 0.1 1 22.0 ± 4.6 0 0.3 17.0 ±4.2 0 1 18.1 ±5.2 0

·· ·· ·· ·· • · · · · · · · · · «»

B-9a 0.03 O, ¹ 0.3 t 1 17 _f 6±1.7 26.7 ±6.1 24.8 ± 3.3 26.8 ± 5.4 0 0 0 0 B-6 °, ³ 13.8 ± 2.4 0 1 22.1 ±6.3 0 B-9b 0.1 18.7 ±5.5 0 op 26.9 ±6.1 0

Example U

Measurement of cardiovascular side effects

Cardiovascular measurements were performed in another group of monkeys using an automated sphygmomanometer model BP 100S (Nippon Colin., Japan). Intravenous (IV) administration of some of the compounds of the present invention at doses 10 to 30 times higher than those used for clonidine and brimonidine did not reduce the working heart rate or lower blood pressure. Interestingly, the compound 4(5)-3-methylthiophen-2-ylmethyl)-1-Himidazole, which showed an intrinsic activity of 0.43 at the alpha2A subtype, had a weak effect on heart rate. Clonidine and brimonidine had a greater effect on heart rate. See Table 3 below.

Table 3. Effects of alpha ₂ -adrenoceptor agonists on cardiovascular variables in conscious Cynomolgus monkeys after IV administration. Measurements were made periodically over a 6-hour period. The number of animals per group was 6 to 10.

J ..Ai...

99

9 9 • « ·'

Tab^ 3 Dose (mg/kg) Maximum decrease from pre-treatment levels (%) Compounds Average arterial blood pressure Heart rate 7 ±4 8 + 3 Clonidine 17 29 + 7 32 + 4 50 35 ±5 50 + 5 Brimonidine 17 36 + 3 52 ±3 50 37 + 5 54 + 3 J-l 17 7 + 5.3 13 + 4 50 4 + 2 6 + 2 167 7 + 5 3 ± 3 500 13 + 3 7 + 4 E-1 17 7±4 11+4 50 7 + 2 14 + 5 167 9 + 4 11+5 C-l 50 12.8 ± 12 tons 12 ±4 500 +5 + 8* +11 ±9* M 500 0.8 + 2.3 5 _{ 5 + 1.9 C-2 500 6.6 + 1.7 ——

C-9

9.4 + 3.0 +9.4 ± l _f 8* 16 ±3.2

3.0 5.0 + 2 _f 3 17 1.0 + 4.1 50 0.1+3.8 500 6.0 ± 2.2

C-3 500 -- 2.3 +2.7 --r- -7-- ÍO.6 ± 3.4 C-8 500 5.5 + 2.7 -/-f- 16.6 ± 1.9 C-5 500 3.9 + 2.8 1 ) 7.1 ±3.9 B-3b 50 2.4 + 4.3 l ¹ 10.0 ±2.8 C-4 500 í i 5.3 + 2.9 -i-.- 1 l 10 _f 9 ± 3 6

• · ·'·'··' * · «' · • ft · · «' · · · ·· · • · · · · · · · · >·· · · • ······ ft · · · · · · · · · · ft · · ft··· ·'·· · ·'· ftft ftft ··

C-7 500 3.0 + 3.9 6.1+3 7 J-2 500 í ¹ +0.6 ±3.1* t i- 6.4 ± 3.3 J-3 500 +10 ±2^1* -f-f— - +10.6 ± 6.0* B-2b 500 5 _f 7±14 6.4 ± 3.6 B-2d 500 +8.9 ± 3.4* i / +15.5 ±3.4* B-9a 500 i i + 10.8 ±3.2* ι 1 +23.8 ±4.4* B-9b 500 ¹ /2.8 ± 1.8 f ( +20.2 ± 3.4* 4(5)-(3- methylthiophene -2-ylmethyl)- IH-imidazole 50 167 9±3 8 ± 6 I I 23 ±4 32 ±8 * vivusP ř tafrcřl Wvetl

Example V

The studies of Examples T and U above demonstrate that the therapeutic effect of alpha2 agonists can be separated from sedative and cardiovascular side effects. This separation can be achieved with compounds that have the property of preferential activity on the alpha2B and alpha2B/alpha2C subtypes, compared to the alpha2A subtype.

Alpha2 adrenergic agonists known in the art that activate all three alpha2 receptors cause sedation, hypotension and bradycardia, which prevents or severely limits their use for the specific treatment of diseases and disorders where these agents have a positive effect. These diseases and disorders include muscle spasticity including hyperactive urinary frequency, diarrhea, micturition, withdrawal syndromes, pain including neuropathic, neurodegenerative diseases including optic neuropathy, spinal cord ischemia and stroke, memory and consciousness disorders, attention disorders, psychosis including manic states, anxiety states, depression, hypertension, congestive heart failure, cardiac ischemia and nasal congestion. See, e.g., Hieble et al., Therapeutic applications of agents interacting with alpha-adrenoceptors, in Alpha-adrenoceptors: molecular biology, biochemistry and pharmacology”. Prog. Basic Clin. Pharmacol. (Basel, Karger) 8, pp. 180220 (1991). For example, clonidine has been found to be clinically effective in the management of postoperative neurogenic and cancer-related pain. However, as Maze and Tranquilli, Maze MB and Tranquilli W. “Alpha-2 adrenoceptor agonists: defining the role in clinical anesthesia,” Anesthesiology 74, 581-605 (1991), point out, the full clinical promise of this and other alpha2 agonists requires the development of compounds that are nonsedating, nonhypertensive, and nonbradycardia-inducing.

• · .44’· ·· 4 4 4 4 ·« · · 4 4 · * * · 4' · · 4 9 4·' .· ’· · 9' '4' 4 44444 44 444 '44 4

4 4 4 4 4 9 4 4 4

4 4 4« 4 9 94 44

The above-listed diseases and disorders can be treated by altivation of the alpha2B or alpha2B/2C receptor subtype(s). Therefore, the alpha2 compounds described above, which are shown to be free of sedative and cardiovascular effects, are useful and advantageous for the treatment of these conditions.

Amelioration of neuronal degeneration in glaucomatous neuropathy is another example of the novel utility of the compounds of the present invention. Recent studies have shown that clonidine and other alpha2 agonists have a neuroprotective effect on retinal cells in a variety of neuronal degenerations observed in rat models. These models include light-induced photoreceptor degeneration in white laboratory rats, as described by Wen et al., Alpha2-adrenergic agonists induce basic fibroblast growth factor expression in photoreceptors in vivo and ameliorate light damage” (Alpha2-adrenergic agonists induce basic fibroblast growth factor expression in photoreceptors in vivo and ameliorate light damage) J. Neurosci. 16, 5986-5992, and calibrated rat optic nerve injury resulting in secondary loss of retinal ganglion cells, as described by Yoles et al., Injury-induced secondary degeneration of rat optic nerve can be attenuated by alpha2-adrenoceptor agonists AGN 191103 and brimonidine”, Invest. Ophthalmol. Vis. Sci. 37, 540, S114. Unlike the compounds of the present invention, however, the doses used in these studies - 0.1 to more than 1 mg/kg by intraperitoneal or intramuscular injection - also had sedative and cardiovascular effects. Induction of basic fibroblast growth factor (bFGF) expression is considered a sensitive indicator of alpha2 receptor activation in the retina (Wen et al., supra) and measurement of bFGF induction following topical administration of alpha2 agonists to the rat eye indicates that approximately 1% of the dose is required to induce 2- to 3-fold levels of bFGF, which is consistent with neuroprotection.

AND.

• 4 4 4 4 4 4 44 444 4 4 4

4 4 '4' 4 · · '· · ·

4'4 4 4'4 44 4'4 4 4 mediated by an alpha2 agonist (see Wen et al., supra, and Lai et al., "Neuroprotective effect of ocular hypotensive agent brimonidine" in Proceedings of the Xlth Congress of the European Society of Ophthalmology (Bologna, Monduzzi Editore), 439-444). These topical doses of conventional alpha2 agonists, such as clonidine, produce systemic side effects such as sedation and hypotension, which preclude their use as ocular neuroprotective agents. Furthermore, co-pending application Ser. No. 08/496,292, filed June 28, 1995, discloses and claims the use of certain nonselective alpha2-adrenergic agents for the treatment of neural damage, the contents of which are incorporated herein by reference in their entirety.

The compounds of the present invention have no sedative or cardiovascular effects after topical administration of at least 3% doses to monkeys. Thus, neuroprotective concentrations of these compounds can be achieved in humans without inducing side effects. In fact, as shown below, the compound of Example B-9(b) has been shown to have neuroprotective effects in the calibrated rat optic nerve injury model of Yolese et al. (see above). See also Table 4, below.

Table 4. Retinal ganglion cell counts 2 weeks after injury (cells/microscope field) Control (vehicle i.p.) Example B-9(b) (0.5 mg/kg i.p.)

33 + 8 73 + 12 n=8 n=5

This level of neuroprotection is comparable to the effect observed in previous studies with the standard alpha2-adrenoceptor agonist, brimonidine, and the neuroprotective agent MK801.

··

i.e.

• · ·· ·· ·· · 9 9 « «· « » · • · · · · ·♦ · · · · · • ····* 9 · · · · · · · • * · · * · '»'··· «·· · ·· ♦· ·'* ··

Example W

Pain relief, including neuropathic pain, is another example of a disorder where the compounds of the invention are useful and advantageous because pain is relieved without undesirable side effects. Clonidine, an agonist that activates all three alpha2 receptors, is used clinically for the treatment of chronic pain, but its utility for this indication is limited because it exhibits sedative and cardiovascular side effects. The compounds of the invention were compared with clonidine and brimonidine in a rodent model of neuropathic pain, which is known to have predictive value for clinical activity. (See, e.g., Kim, S. and Chung, J. "An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat" Pain 50, pp. 355-363 (1992). After ligation of two spinal nerves, animals develop sensitivity to normally non-painful stimuli, such as touch. The ability of the alpha2 compounds to abolish this sensitivity, which is called allodynia, was tested 30 minutes after dosing the compound intrathecally or intraperitoneally. The inhibitory activity of each compound was also measured in an activity chamber. The compounds of the present invention, such as compound N-1, are able to inhibit allodynia without having a sedative effect, even at very high doses. This contrasts with clonidine and brimonidine, which have a sedative effect at doses only slightly higher than their anti-allodynic doses. See Tables 5 and 6, below.

• · · · 9 9 9 9 *' * ·

9 9 * · ·· '· · · · • ···· · · · 9 9 9 9 '· · 9 φ · · · 9 9 9 9 ·

9 9 99 ·· ·'*' ··

Table 5. Anti-allodynic and sedative effects of alpha2-adrenoceptor agonists in rats 30 minutes after intrathecal administration (N=6).

Compound Dose (microgram) Abolition of tactile allodynia (%) Attenuation (%)

Clonidine 0.1 20* ND 1 96* 15 10 ND 60* N-1 3 13 ND 30 64* 0 300 ND 0

*p<0.05 compared to control (saline) • ND means not determined

Table 6. Anti-allodynic and sedative effects of alpha2-adrenoceptor agonists in rats 30 minutes after intraperitoneal administration (N=6).

Compound Dose (mg/kg) Abrogation of tactile allodynia (%) Attenuation (%)

Brimonidine 3 0 ND 30 37* 24 300 ND 67* N-1 3 3 ND 30 41* ND 10,000 ND 0 * p<0.05 compared with control (saline)

• ND means not specified

The results of these Examples demonstrate that the common side effects of alpha2-adrenoceptor drugs are mediated by the alpha2A subtype, and that their ocular antihypertensive and other therapeutic effects may be mediated by a subtype other than the alpha2A subtype. Thus, alpha2-adrenoceptor agents belonging to different structural groups that share a low functional activity at the alpha2A subtype lower IOP and produce other therapeutic effects without exhibiting dose-limiting side effects.

While a specific embodiment of the present invention is described, it is understood that the invention is not limited to this embodiment, as many obvious modifications can be made, and • · · ·' φφ ·· Φ· tt 8 · 4 » < · · ·' ·'

8 8 9 8 88 8 8 8 8 • ······ ·· · Φ · · · 8

9 9 8 8 8 9 8 φ

ΦΦ · 8 8 9 8 88 9 8 the authors include in this invention any such modification that comes within the scope of the appended claims.

Having described the invention, we formulate the following patent claims.

Industrial applicability

The invention relates to a method of treating animals of mammalian species, including humans, using a pharmaceutical composition comprising as an active ingredient one or more compounds having the effect of specific or selective alpha2B or alpha2B/2C agonists, used for the therapy of many diseases or conditions for which alpha adrenergic compounds are useful, including but not limited to glaucoma, reduction of intraocular pressure, chronic pain, diarrhea and nasal congestion. Furthermore, the compounds of the invention are useful for the treatment of muscle spasticity including hyperactive frequent urination, diarrhea, urination, withdrawal syndromes, pain including neuropathic, neurodegenerative diseases including optic neuropathy, spinal cord ischemia and stroke, memory and consciousness disorders, attention disorders, psychosis including manic states, anxiety states, depression, hypertension, congestive heart failure, cardiac ischemia and nasal congestion.

This invention also includes pharmaceutical compositions used in the above-described method of treatment and relates particularly to a method of treating diseases and conditions in which adrenergic compounds are useful but their use is limited due to known adverse effects.

Claims (93)

PATENT CLAIMS kooo -γγ 1. A compound having selective agonist activity at the alpha2B or alpha2B/alpha2C adrenergic receptor subtype(s) compared to the 2A adrenergic receptor subtype represented by the general formula I where dotted lines indicate preferred double bonds; R is H or lower alkyl; X is S or C(H)R ¹ , where R ¹ is H or lower alkyl or R ¹ is absent when X is S or when the bond between X and the ring represented is a double bond; Y is O, N, S, (CR ¹ x) _yi where y is an integer from 1 to 3, -CH=CH- or -Y ¹ CH ₂ -, where Y ¹ is O, N or S; x is an integer having a value of 1 or 2, where x is 1 if R ² , R ³ or R ⁴ are bonded to an unsaturated carbon atom and x is 2 if R ² , R ³ or R ⁴ are bonded to a saturated carbon atom; R ² is H, lower alkyl, halogen, hydroxy or lower alkoxy, or, if attached to a saturated carbon atom, R ² may be oxo; R ³ and R ⁴ are each H, lower alkyl, hydroxy, lower alkoxy, or phenyl or, together, are 100 ♦ · φ· » » » · • · ·♦ » · • · • · • · • · · ·. -(C(R ² )x)z-; -Y ¹ (C(R ² )x)z'; -Y ¹ (C(R ² )x)yY ¹ -; -(C(R ² )x)-Y ¹ -(C(R ² )x)-; -(C(R ² )x)-Y ¹ - (C(R ² )x)(C(R ² )x)- and -Y ¹ -(C(R ² )x)-Y ¹ -(C(R ² )x)- where z is an integer from 3 to 5, z' is an integer from 2 to 4 and χ and y are as defined above, and further each of the ends of all these divalent parts of the molecule may be connected to R ³ or R ⁴ to form a fused cyclic structure and the ring thus formed may be fully unsaturated, partially unsaturated or fully saturated, provided that the carbon atom in the ring does not have more than 4 valences, the nitrogen atom does not have more than 3 valences and O and S do not have more than 2 valences, including pharmaceutically acceptable salts of said compound. 2. The compound of claim 1 wherein said compound is represented by the general formula 3. A compound according to claim 2 wherein X is C(H)R ¹ . 4. A compound according to claim 3 wherein R ¹ is H. 101 4 4 44 44 4 4 44 44 · 4 4 4 4 4' 4 4 9 4 4 4 4 4 44 4 4 4 4 4 4 • 4 4 4 '4 4 4 4 • 44 4 44 '9 4 44 44 5. A compound according to claim 4 wherein R ² is H and represents a furanyl radical. 6. A compound according to claim 5 wherein R ³ and R ⁴ are (CH) 4 . 7. A compound according to claim 5 wherein R ³ is H and R ⁴ is t-butyl. 8. A compound according to claim 5 wherein R ³ and R ⁴ are H. 9. A compound according to claim 5 wherein R ³ is H and R ⁴ is methyl or ethyl. 10. A compound according to claim 4 wherein R ² is H and represents a thienyl radical. 11. A compound according to claim 10 wherein R ³ and R ⁴ represent (ChhH 12. A compound according to claim 10 wherein R ³ is phenyl and R ⁴ is H. 13. A compound according to claim 10 wherein R ³ and R ⁴ represent (CH 2 ) . 102 14. A compound according to claim 10 wherein R ³ and R ⁴ are H. 15. A compound according to claim 10 wherein R ³ and R ⁴ represent (CH) ₄ . 16. A compound according to claim 10 wherein R ³ is H and R ⁴ is methyl. 17. A compound according to claim 10 wherein R ³ is bromo and R ⁴ is H. 18. A compound according to claim 4 wherein represents a cyclohexyl radical. 19. A compound according to claim 18 wherein R ² is H and R ³ and R ⁴ represent (CH) 4 . 20. A compound according to claim 18 wherein R ² is H and R ³ and R ⁴ represent (CH) 2 S. 21. A compound according to claim 18 wherein R ² is H and R ³ and R ⁴ represent (CH 2 ) 4 . 22. A compound according to claim 18 wherein R ² is dimethyl and R ³ and R ⁴ represent (CH) 4 . 23. A compound according to claim 18 wherein Y is -CH ₂ CH(CH 3 )-, R ² is hydrogen or an oxo group, and R ³ and R ⁴ represent (CH) 4 . 103 9· 99 9 9 « 9 9 99 99 99 9 9 * « 9 9 9 · • *9 · 9 · 9 9 24. A compound according to claim 18 wherein R ² is oxo and R ³ and R ⁴ represent S(CH) 2 25 . A compound according to claim 18 wherein Y is -CH 2 C(CH 3 ) 2 -, R ² is hydrogen or an oxo group and R ³ and R ⁴ represent (CH) ₄ . 26. A compound according to claim 18 wherein R ² is an oxo group and R ³ and R ⁴ are (CH) ₄ . 27. A compound according to claim 18 wherein R ² is an oxo group and R ³ and R ⁴ represent (CH) ₂ C(OCH ₃ )CH. 28. A compound according to claim 4 wherein Y represents a cyclopentyl radical. 29. A compound according to claim 28 wherein R ² is H and R ³ and R ⁴ represent (CH) ₄ . 30. A compound according to claim 28 wherein R ² is hydrogen and R ³ and R ⁴ represent (CH ₂ ) 3· 31. A compound according to claim 4 wherein 104 in/year 4 ♦ 4* 4* 44 44 • 4 4 • • 4 4 4 4 4 4 4 4 4 • • 4 * · 4 4 4 4 4 • 4 4 • · 4 4 44 · • ·· 4 4 44 4» represents the benzyl radical. 32. A compound according to claim 31 wherein R ² , R ³ and R ⁴ are H. 33. The compound of claim 1, wherein said chemical has the general formula 34. A compound according to claim 33 wherein X is C(H)R ¹ and R, R ¹ , R ² , R ³ and R ⁴ are H. 35. A compound according to claim 34 wherein Y is O. 36. A compound according to claim 35 wherein Y is S. 37. The compound of claim 1 wherein said chemical has the general formula 105 ©· ·ί ·* ·· ··€· · · * · 9 · ·* 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 99 99 99 99 elephant • * ···* · 38. A compound according to claim 37 wherein R ³ and R ⁴ represent (CH) 4 . 39. A compound according to claim 38 wherein Y ¹ is O. 40. A compound according to claim 39 wherein R ¹ is an oxo group. 41. A compound according to claim 40 wherein X is CH. 42. A compound according to claim 40 wherein X is CH2. 43. A compound according to claim 39 wherein one of R ² is a hydroxy group and the other is H. 44. A compound according to claim 39 wherein R ² is H. 45. A compound according to claim 38 wherein Y ¹ is S. 46. A compound according to claim 45 wherein X is CH2. 47. A compound according to claim 46 wherein R ² is an oxo group. 48. A compound according to claim 46 wherein R ² is H. 49. A compound according to claim 45 wherein X is CH and R ² is an oxo group. 50. A compound according to claim 3 wherein Y is (CH ₂ ) 3· 106 • · • · *; · · · · r . 51. A compound according to claim 50 wherein X is CH and R ² is an oxo group. 52. A compound according to claim 50 wherein X is CH ₂ and R ² is H. 53. A compound according to claim 2 wherein X is S and is phenyl. 54. A compound according to claim 3 wherein R ¹ is methyl and is furanyl. 55. A compound according to claim 4 wherein Y is CH ₂ (CR ¹ 2) ₂ wherein R ¹ is hydrogen or methyl. 56. A compound according to claim 55 wherein R ² is H. 57. A compound according to claim 55 wherein R ² is an oxo group. 107 iii ·' · 58. A compound according to claim 3 wherein R is CH3, represents a phenyl radical and ^R3 and ^R4 represent O( _CR2 )2O. 59. A compound according to claim 2 wherein X is CH, Y represents a cyclopentyl radical and R 2 is an oxo group. 60. A compound represented by the formula 61. The compound of claim 1 represented by the general formula 108 where Y is (R ¹ X)2, R ³ +R ⁴ is (C(R ² ) _X )4 and X is attached at one of the two positions of the ring, as shown by the wavy line, with the remaining position occupied by hydrogen, provided that two double bonds cannot occupy the same ring atom. 62. The compound of claim 61, wherein said compound is represented by the general formula wherein (R ² ) _X is hydrogen or an oxo group. 63. The compound of claim 61, wherein the structure is 64. A compound according to claim 62 wherein the structure is 65. A compound according to claim 2 wherein R is hydrogen, R ³ +R ⁴ are -(C(R ² )X)-N-(C(R ² )X)-(C(R ² ) _X )- and X is CHR ¹ as represented by the general formula 109 ft · N. // NH The -CHR' group CHR ¹ attaches at one of the two ring positions, as shown by the wavy line, with the remaining position occupied by hydrogen, and with the proviso that two double bonds may not occupy the same ring atom. 66. A compound according to claim 65 wherein said compound has the general formula and (R ² ) _x is hydrogen or an oxo group. 67. A compound according to claim 65 wherein said compound has the general formula and (R2) _X is hydrogen or an oxo group. 68. A compound according to claim 1 wherein R ³ +R ⁴ are selected from the group consisting of -Y ¹ -(C(R ² )x)(C(R ² )x)-Y ¹ - and -Y ¹ (C(R ² )x)-(C(R ² )x)-(C(R ² )x)- and Y ¹ is N or O or S as represented by the general formula 110 f where X and X' are selected from the group consisting of N, O and C and at least one of X and X' is N. 69. The compound of claim 68 wherein said compound is represented by the general formula wherein (R ² )x is hydrogen or an oxo group. 70. The compound of claim 68, wherein said compound is represented by the general formula wherein (R ² )x is hydrogen or an oxo group. 71. A compound having selective agonist activity at the alpha2B or alpha2B/2C adrenergic receptor or at the alpha2B and alpha2C adrenergic receptor subtype(s), compared to the alpha2A adrenergic receptor subtype, represented by the formula 111 • · and its pharmaceutically acceptable salts. 72. A method of administering a pharmaceutical composition to a mammalian host, including a human, comprising administering a pharmaceutical composition comprising an effective dose of an active compound for treating or preventing glaucoma without sedative or cardiovascular side effects, wherein said compound has adrenergic activity and is a selective agonist of the alpha2B adrenoceptor subtype or the alpha2B/alpha2C adrenoceptor subtype(s) in preference to the alpha2A adrenoceptor subtype. 73. The method of claim 72, wherein the active compound has a potency comparable to a standard full agonist that is at least 0.3 higher on the alpha2B or alpha2C adrenoceptor subtypes compared to the alpha2A adrenoceptor subtype, and its potency on the alpha2A adrenoceptor subtype is less than or equal to 0.4. 74. The method of claim 72, wherein the active compound is at least ten times more potent for the alpha2B or alpha2C adrenoceptor subtype than for the alpha2A adrenoceptor receptor. 112 75. The method of claim 74, wherein about 0.001 to 5% by weight of the active compound is administered topically to the mammalian host once or twice daily. 76. The method of claim 75, wherein about 0.01 to 3% by weight of the active compound is administered topically to the mammalian host once or twice daily. 77. The method of claim 72, wherein said compound has no activity at the alpha 2A adrenoreceptor subtype. 78. The method of claim 72, wherein said compound has no activity at the alpha 2A and alpha 2C adrenoreceptor subtypes. 79. A method of administering a pharmaceutical composition to a mammalian host, including a human, comprising administering a pharmaceutical composition comprising an effective dose of an active compound for the treatment of elevated intraocular pressure without sedative or cardiovascular side effects, wherein the compound has adrenergic activity and is a selective agonist of the alpha 2B or alpha 2B/alpha 2C adrenoceptor subtype(s) in preference to the alpha adrenoceptor receptor subtype. 2A. 80. The method of claim 79, wherein the active compound has potency comparable to a standard full agonist that is at least 0.3 times greater at the alpha 2B or 2C adrenoceptor subtypes than at the alpha 1 adrenoceptor subtype. 113 ·· subtype alpha 2A, and its potency on the adrenoceptor subtype alpha 2A is less than or equal to 0.4. 81. The method of claim 80, wherein 0.001 to 5% by weight of the active compound is administered topically to the mammalian host once or twice daily. 82. The method of claim 81, wherein 0.01 to 3.0% by weight of the active compound is administered topically to the mammalian host once or twice daily. 83. The method of claim 79, wherein said compound has no activity on alpha2A adrenoreceptor subtypes. 84. The method of claim 79, wherein said compound has no activity at the alpha2A and alpha2C adrenoreceptor subtypes. 85. A method of treating a mammal, characterized in that it reduces intraocular pressure without cardiovascular and sedative side effects by selectively agonizing the alpha2B adrenoceptor subtype or the alpha2B/alpha2C adrenoceptor subtype(s) in preference to the alpha2A adrenoceptor subtype. 86. A method for selectively agonizing the alpha2B adrenoceptor subtype or the alpha2B/alpha2C adrenoceptor subtypes without agonizing the alpha2A adrenoceptor subtype, comprising administering a therapeutically effective 114 amount of selective agonist(s) of the alpha2B or alpha2B/alpha2C receptor subtype. 87. An alpha adrenergic agonist, characterized in that it selectively activates the alpha2B or alpha2B/alpha2C receptor subtype(s) in preference to the alpha2A receptor subtype. 88. The method of claims 72, 79, 85 or 91, wherein the active compound is selected from the group consisting of compounds of the general formula wherein the dotted lines represent preferred double bonds; R is H or lower alkyl; X is S or C(H)R ¹ , where R ¹ is H or lower alkyl or R ¹ is absent if X is S or when the bond between X and the ring represented is a double bond; Y is O, N, S, (CR ¹ x) _y , where y is an integer from 1 to 3, -CH=CH- or Y ¹ CH ₂ - where Y ¹ is O, N or S; x is 1 or 2, where x is 1 when R ² , R ³ or R ⁴ are bonded to an unsaturated carbon atom and x is 2 when R ² , R ³ or R ⁴ are bonded to a saturated carbon atom; R ² is H, lower alkyl, halogen, hydroxy or lower alkoxy, or, if R ² is attached to a saturated carbon atom, it may be an oxo group; R ³ and R ⁴ are 115 • 4 4 4 4 4· both Η, lower alkyl, hydroxy, lower alkoxy or phenyl, or, together are -(C(R ² )x)z-; Y ¹ (C(R ² )x)z'-; -Y ¹ (C(R ² )x)yY ¹ ; -C(R ² )x)-Y ¹ -(C(R ² )x)-; -(C(R ² )x)-Y ¹ -(C(R ² )x)-(C(R ² )x)- andY ¹ (C(R ² )x)-Y ¹ -(C(R ² )x)-, where z is an integer from 3 to 5, z' is an integer from 2 to 4 and x and a are as defined above, and further both ends of all these divalent moieties of the molecule may be attached to either R ³ or R ⁴ to form a fused ring structure and the ring thus formed may be fully unsaturated, partially saturated or fully saturated, provided that the carbon in the ring has no more than 4 valences, the nitrogen has no more than 3 valences and O and S have no more than 2 valences; or where W is a bicyclic radical selected from the group consisting of 116 4 ·4 44 4· ·· 4 4 <4 4 4 4' · 4 4 4 « · 444 4 44 4 4444 44 · · 444 44 4 where R ⁵ , R ⁶ , R ⁷ and R ⁸ are selected from the group consisting of H and lower alkyl, provided that at least one of R ⁵ and R ⁶ or R ⁶ and R ⁷ is OC(R ⁹ )C(R ⁹ )N(R) and forms a fused ring with where R ⁹ is H, lower alkyl or oxo and where R ¹⁰ is H, lower alkyl, phenyl or lower alkyl substituted phenyl and Z is O or NH. 89. A method of administering a pharmaceutical composition comprising an effective dose of an active compound with adrenergic activity to a mammalian host, including a human, for the treatment or prevention of glaucoma, wherein the active compound has the biological property of being a selective agonist of the alpha2B or alpha2B/alpha2C receptor subtype(s) in preference to the alpha2A receptor subtype, said selectivity being measured by an assay using cells that naturally express the individual alpha2 subtypes or have one of the subtypes introduced, the receptors being human or from a species shown to have the same pharmacological properties, and in said assay the potency of the active compound relative to a standard compound measured at the alpha2B or alpha 2C receptor subtype is determined to be at least 0.3 greater than the potency of the active compound relative to the standard compound 117 the compound measured at the alpha2A receptor subtype, and its potency at the alpha2A receptor subtype is less than or equal to 0.4, and/or the active compound is at least 10-fold more potent at the alpha2B or alpha2C receptor subtypes than at the alpha2A receptor subtype. 90. The method of claim 89, wherein 0.001 to 5% by weight of the active compound is administered topically to the mammalian host organism per day. 91. A method of administering a pharmaceutical composition comprising an effective dose of an active compound to a mammalian host, including a human, for the treatment or prevention of muscle spasticity including hyperactive urinary frequency, diarrhea, urination, withdrawal syndromes, pain including neuropathic, neurodegenerative diseases including optic neuropathy, spinal cord ischemia and stroke, memory and consciousness disorders, attention disorders, psychosis including manic states, anxiety states, depression, hypertension, congestive heart failure, cardiac ischemia and nasal congestion without sedative or cardiovascular side effects, characterized in that said compound has adrenergic activity and is a selective agonist of the alpha2B or alpha2B/alpha2C adrenoceptor receptor subtype(s) in preference to the alpha2A adrenoceptor receptor subtype. 92. A method of administering a pharmaceutical composition comprising an effective dose of an active compound having adrenergic activity to a mammalian host, including a human, for the treatment of muscle spasticity including hyperactive urinary frequency, diarrhea, urination, withdrawal syndromes, pain, including neuropathic, neurodegenerative diseases 118 • φ φφ φφ Φ· φφ φφφφ >φ φφφ: φ φ φ φ φ· · φ φ φφ φ φ · φ one of the subtypes is introduced, the receptors being human or from a species shown to have the same pharmacological properties, and in this assay the potency of the active compound relative to the standard compound measured at the alpha2B or alpha 2C receptor subtype is determined to be at least 0.3 times greater than the potency of the active compound relative to the standard compound measured at the alpha2A receptor subtype, and its potency at the alpha2A receptor subtype is less than or equal to 0.4, and/or the active compound is at least 10 times more potent at the alpha2B or alpha2C receptor subtypes than at the alpha2A receptor subtype. 93. A method of administering a pharmaceutical composition comprising an effective dose of an active compound having adrenergic activity to a mammalian host, including a human, for the treatment of muscle spasticity including hyperactive urinary frequency, diarrhea, urination, withdrawal syndromes, pain including neuropathic, neurodegenerative diseases including optic neuropathy, spinal cord ischemia and stroke, memory and consciousness disorders, attention disorders, psychosis including manic states, anxiety states, depression, hypertension, congestive heart failure, cardiac ischemia and nasal congestion without sedative or cardiovascular side effects, characterized in that the active 119 99 ·· ·· 99 9 '9 9 9 9 9 9: 9 9 · 99 9 · · · • · 9 9 9 9 '9 9 · • · · · · · · · 9 9 9 9 9 9 9 9 the compound has the biological property of being a selective agonist of the alpha2B or alpha2B/alpha2C receptor subtype(s) in preference to the alpha2A receptor subtype, and said selectivity is measured by an RSAT assay, wherein activation of the alpha2A and alpha2C receptor subtypes by the test compound is compared to brimonidine and activation of the alpha2B receptor subtype is compared to oxymetazoline, and wherein the respective alpha2A, alpha2B and alpha2C receptor subtypes are expressed in NIH-3T3 cells, and in said assay the potency of the active compound on the alpha2C receptor subtype relative to the effect of brimonidine or the potency of the active compound on the alpha2B receptor subtype relative to the effect of oxymetazoline is determined to be at least 0.3 greater than the potency of the active compound on the alpha2A receptor subtype relative to the effect of brimonidine, and its potency at the alpha2A receptor subtype is less than or equal to 0.4 and/or the active compound is at least 10 times more potent at the alpha2B or alpha2C receptor subtypes than at the alpha2A receptor subtype. 94. The method of claim 74, wherein the active compound is at least 100 times more potent at the alpha2B or alpha2C adrenoceptor subtype than at the alpha2A adrenoceptor subtype.